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An overview of the innate immune system

An overview of the innate immune system
Richard B Johnston, Jr, MD
Section Editor:
Rebecca Marsh, MD
Deputy Editor:
Anna M Feldweg, MD
Literature review current through: Nov 2022. | This topic last updated: Mar 05, 2021.

INTRODUCTION — Humans live in an environment teeming with micro-organisms and could not exist as a species without highly effective mechanisms of host defense. The innate immune system constitutes the first-line barrier, the rapid-response mechanism, to prevent microbial invasion. Its components are inherited from parent to child and directed against molecules expressed only by micro-organisms. These host defense components are evolutionarily ancient, found in all multicellular organisms, and expressed in humans as conserved elements (homologs) shared with other vertebrates and, in some form, with insects and plants [1-5].

This topic will review the cells, proteins, and receptors that comprise the innate immune system, the functional differences between innate and acquired immune responses, and the mechanisms by which the two systems interact. Disorders of innate immunity and more specific topics on individual types of cells and receptors are presented separately. (See "Toll-like receptors: Roles in disease and therapy" and "Complement pathways".)

INNATE, ADAPTIVE, AND TRAINED INNATE IMMUNITY — Medzhitov and Janeway defined innate immunity as a system of rapid immune responses that are present from birth and not adapted or permanently heightened as a result of exposure to micro-organisms, in contrast to the responses of T and B lymphocytes in the adaptive immune system [6-8]. The importance of such a system can be appreciated by considering that the generation time of most bacteria is 20 to 30 minutes, whereas the development of a specific adaptive immune response with antibody and T cells takes days to weeks. The innate immune system protects the host during the time between microbe exposure and initial adaptive responses.

The innate immune system recognizes microbes directly through pattern recognition receptors (PRRs), which are receptors specific for molecular components of micro-organisms that are not made by the host. The genes encoding PRRs are transmitted from parent to offspring. Phylogenetic studies have indicated that genes for PRRs and other components of the innate immune system have been gradually modified over generations by natural selection [1,7,8].

In contrast, each T and B lymphocyte acquires a structurally unique receptor during development, yielding a vast repertoire of cells with individualized receptors. From this repertoire, cells exposed to their unique microbial or other foreign antigen expand as a clone of cells directed at that specific antigen. As the clone expands, the tightness (affinity) of the binding and the specificity for its particular antigen both increase. Thus, the most useful receptors are selected and improved in the host over time. However, the "learned" immune responses and refinements made to the adaptive system cannot be passed on to an individual's progeny. (See "The adaptive cellular immune response: T cells and cytokines" and "The adaptive humoral immune response".)

Research since Medzhitov and Janeway has significantly expanded the understanding of innate immunity. The principle of "cross protection" in host defense was demonstrated in the 1960s. Innate macrophages that had been "activated" during infection to one pathogen were modified so that they could more effectively kill a second, unrelated organism. This heightened state waned rapidly once the pathogen (primary stimulus) was eliminated [9]. Later work showed that macrophages could be "primed" (imprinted) for enhanced expression of microbicidal mechanisms and pathogen killing by exposure to microbial components such as lipopolysaccharide (LPS) [10], and that small amounts of LPS can prime neutrophils for increased expression of microbicidal mechanisms on exposure to a variety of stimuli [11].

It is now clear that cells of the innate immune system can be trained by past infection, exposure to vaccines such as bacille Calmette-Guérin (BCG), or contact with microbial components such as LPS so that they have an enhanced response to the original or another trigger. The trained state is conferred by epigenetic reprogramming of transcriptional pathways, not gene recombination [12-15]. The lifespan of trained monocytes and neutrophils is short, but marrow hematopoietic stem cells (HSCs) can conserve epigenetic memory of previous infections and are long-lived, with self-renewal properties that maintain lifelong production of innate immune cells [16].

The principle of cross protection as expressed by trained innate immune cells has obvious implications for clinical medicine [17]. Randomized trials in Guinea-Bissau have shown that BCG vaccine administered at birth to low-weight infants significantly reduced death from infectious disease within the first month and first year of life [18]. BCG given to volunteers four weeks prior to administration of yellow fever vaccine significantly reduced the viral load after inoculation with the vaccine virus [19]. Trained innate immunity harnessed in this way has the potential to aid cancer therapies, sepsis-associated immune paralysis, and perhaps even resistance to novel viral outbreaks such as that by SARS-CoV-2 [20]. Large-scale epidemiological studies suggest that national programs in BCG vaccination reduce the mortality of COVID-19 [21,22]. National programs in vaccination with BCG, measles, or oral polio vaccine have decreased all-cause mortality or respiratory infections in adolescents or older adults [23].

The inflammatory response that is essential for resistance to infection is abated by an anti-inflammatory response as the host begins to win the battle. In this same sense, epigenetic changes like those that drive protective cross-specific immunity drive an antigen-nonspecific suppression of immunity. Although this response is useful in the short term, its persistence has the potential to dampen the response to future antigen-nonspecific infection [23].

COMPONENTS OF INNATE IMMUNITY — Components of the innate immune system include those of the host itself and also its resident microbes, the microbiome. Embedded in the list of host components below is a vast array of cells, receptors, and molecules that are involved in eliminating enemies of host survival and a similar spectrum of components involved in returning the body's physiology to its baseline. These elements are grouped into units of biological function that capture the extraordinary breadth of mechanisms that evolution has brought forward as the system of innate immunity.  

Host components

Physical barriers – Tight junctions between skin cells, epithelial and mucous membrane surfaces, mucus itself, and blood vessel endothelial cells that prevent pathogen penetration of the intestines [24-27].

Antimicrobial enzymes in epithelial and phagocytic cells (eg, lysozyme).

Inflammation-related serum proteins (eg, complement components, C-reactive protein [CRP], and lectins [carbohydrate-binding proteins]).

Antimicrobial peptides (AMPs) (defensins, cathelicidins, and many more) on the surfaces of cells and within phagocyte granules.

Cell receptors that sense micro-organisms and signal a defensive response (eg, toll-like receptors [TLRs]).

Cells that release cytokines and other mediators of the inflammatory response (eg, macrophages, mast cells, natural killer [NK] cells, innate lymphoid cells [ILCs]).

Cytokines, cell-cell communicating and signaling proteins that mediate and regulate immunity, inflammation, and hematopoiesis, including chemokines, interferons (IFNs), interleukins (ILs), lymphokines, and tumor necrosis factor (TNF) [28].

Phagocytes (neutrophils, monocytes, macrophages).

The inflammasome, a central signaling system that regulates the innate inflammatory response.

The microbiome.

The microbiome — The microbiome, the collection of bacteria, fungi, and viruses that live in and on the body, may also be considered a component of the innate immune system, as it profoundly impacts mechanisms of host defense [29-43]. The body's microbial composition directly influences the maturation of the immune response and its continued effectiveness, protects against pathogen overgrowth, and modulates the balance between inflammation and immune homeostasis [34,44-48]. For example, skin microbes interact with the immune system to promote wound healing [49]. Non-pathogenic coagulase-negative staphylococci on the skin produce an antimicrobial peptide that can inhibit growth of pathogenic Staphylococcus aureus. These protective strains are deficient in atopic dermatitis [50]. There are now convincing data that the gut microbiome influences the nervous system, and there are efforts to determine the mechanism and to develop brain drugs [51-53].

The term "dysbiosis" refers to a change in the composition, diversity, or metabolites of the microbiome from a healthy pattern to a pattern associated with disease or a predisposition to disease, including Crohn disease and ulcerative colitis [34-36,54-61]. Antibiotic use is the classic cause, and Clostridioides difficile infection is a common, serious expression. Fecal microbiota transplantation (FMT) has been an effective method of treatment, though not without risk [62-65]. FMT has also improved remission rates of inflammatory bowel disease and chronic bacterial vaginosis [64-68]. In plant systems, healthy soils have a microbiome that suppresses the invasion of plant root pathogens [69-71]. (See "Treatment of irritable bowel syndrome in adults", section on 'Other therapies'.)

Dysbiosis is believed to play a role in development of obesity, type 2 diabetes, food allergy, asthma, and atopic dermatitis [35,46,72-74]. Because of its role as an orchestrator of biologic processes, the microbiome offers an attractive target for therapeutic intervention [75]. Manipulation of the gut microbiome through dietary change has been used with some success to treat type 2 diabetes [76,77] and malnourished children [78,79].

CRITICAL FUNCTIONS — Essential functions of the innate immune system include the following:

Detection of micro-organisms and first-line defense against invasion and infection. (See 'Microbial detection through pattern recognition' below.)

Maintenance of "immunologic homeostasis," the balance between the proinflammatory mechanisms of host defense and the anti-inflammatory responses that return the host to a healthy baseline. The cardinal signs of inflammation (tumor, rubor, calor, and dolor [swelling, redness, heat, and pain]) are products of the protective action of innate immunity. To limit damage to the host, these responses must also be terminated when no longer needed. (See 'Homeostasis in the innate immune system' below.)

Activation and instruction of adaptive immune responses.

MICROBIAL DETECTION THROUGH PATTERN RECOGNITION — Innate immune responses to infection are largely mediated by a variety of proteins that recognize and interact with components that are specific to microbes. These proteins are grouped in their broad biologic context as "pattern recognition receptors" (PRRs) to emphasize their common function in host defense. The molecular components of micro-organisms recognized by PRRs are called pathogen-associated molecular patterns (PAMPs). These receptors also recognize damage-associated molecular patterns (DAMPS) released as a consequence of tissue injury from inflammation or other causes.

Pathogen-associated molecular patterns (PAMPs) — PRRs are capable of distinguishing between self-tissues and microbes by recognizing highly-conserved PAMPs. Each type of PAMP is characteristic of a specific group of microbes.

PAMPs have certain features in common:

PAMPs are produced only by microbes.

PAMPs are typically invariant structures shared by entire classes of pathogens.

PAMP structures are usually fundamental to the integrity, survival, and pathogenicity of the micro-organisms, such that a microbe cannot mutate its PAMPs to avoid the host's defense mechanisms and still survive.

Bacterial endotoxin (lipopolysaccharide, LPS), a component of the outer membrane of all gram-negative bacteria, is a prototypical PAMP. Endotoxin contains lipid A, a highly conserved structure of the lipid bilayer of the outer bacterial cell membrane that confers many of endotoxin's biologic activities [80]. Lipid A specifically interacts with TLR4 (see 'Toll-like receptors' below). Other examples of PAMPs include the following:

Membrane components common to large categories of bacteria, such as peptidoglycan, lipoteichoic acids, and mannans.

Unmethylated microbial DNA.

Double-stranded RNA of viral origin.

Glucans, polysaccharides, or proteins that are common to microbes but not to animals or humans.

Damage-associated molecular patterns (DAMPs) — DAMPs or "alarmins" are nuclear, mitochondrial, or cytosolic molecules released from host cells as a result of infection, tissue injury, or cell necrosis. These molecules include high mobility group box 1 (HMGB1), S100 proteins, heat-shock proteins, and adenosine triphosphate (ATP). Once released extracellularly, alarmins are recognized by PRRs on cells of the innate immune system, which promotes their removal but activates them to release proinflammatory cytokines that can promote serious illness, even sepsis syndrome [81,82].  

Pattern recognition receptors (PRRs) — PRRs can be divided into two broad groups: Secreted and circulating proteins and peptides and transmembrane and intracellular signal-transducing receptors (receptors in the more traditional sense). Some of the best studied molecules are discussed here.

Secreted and circulating PRRs — Secreted and circulating pattern recognition molecules include antimicrobial peptides (AMPs), collectins, lectins, pentraxins, and C1q of the complement system. These proteins and peptides mediate direct microbial killing, act as helper proteins for transmembrane receptors, and function as enhancers of phagocytosis (opsonins) by immune effector cells. Prototypic secreted and circulating PRRs include the following (table 1):

The complement system — The first component of complement, C1q is a circulating and cell-associated pattern recognition receptor (PRR) that plays a broad role in host protection. When C1q binds to antibody that is fixed to a microbe, to damaged cells or tissues, or to immune complexes, it triggers the complement cascade, a key effector system of the innate immune response. The resulting attachment of C3b opsonizes (promotes phagocytosis of) the microbe or particle, generates chemotactic factors, and triggers fixation of the later-acting components that comprise the membrane-attack complex, which can directly lyse some microbes [83,84]. Complement activation is not confined to the extracellular space but also occurs within immune cells to stabilize intracellular metabolism in the basal state or during response to infection [85,86]. Because complement's potent inflammatory response to infection is also deployed when it is triggered by the immune complexes or autoantibodies of collagen-vascular disease or in other inflammatory conditions, the system is the target of intense investigation into possible therapeutic interventions [84,87-89]. (See 'Collectins' below and "Complement pathways".)

Antimicrobial peptides — Antimicrobial peptides (AMPs) are a group of secreted pattern recognition receptors (PRRs) that are important in the protection of the skin and mucosal membranes and in the killing of phagocytosed organisms. AMPs secreted onto epithelial surfaces at a site of injury create a microbicidal shield that damages micro-organisms prior to attachment and invasion. They function synergistically and are microbicidal against a broad range of bacteria, fungi, chlamydiae, parasites, and enveloped viruses [43,90-104]. They are strategically placed anatomically; eg, single-cell RNA sequencing of the kidney shows transcripts for AMPs in the pelvic epithelium where exposure to potential pathogens is high [105].

Petrolatum, commonly used in the management of atopic dermatitis, increases the concentration of AMPs in the skin to which it is applied [106]. A database of over 1200 AMPs published in 2009 links amino acid composition to activity against specific types of micro-organisms [101].

AMPs form pores through the outer membranes of a microbe that disrupt the membrane integrity and lead to death of the microbe. AMPs exist in many different forms and structures, but all contain clusters of hydrophobic, cationic (positively charged) amino acids that bind to negatively charged phospholipids in the outer bilayer of bacterial membranes. The outer cell membranes of animals contain lipids (including cholesterol) that differ from those of microbes, and AMPs are not attracted to them. Families of AMPs include the following:

Defensins, which are divided into alpha- and beta-defensins:

Human alpha-defensins 1 to 4 (HDs 1 to 4) are contained in the azurophilic granules of neutrophils and are also synthesized by Paneth cells at the base of small intestinal crypts (alpha-defensins 5 and 6) [92,94,96,107]. Defensins are short peptides (30 to 45 amino acids) that have three disulfide bonds that protect the peptide from protease degradation. They comprise 2 to 4 percent of the neutrophil cellular protein and are released into the phagocytic vacuole with captured organisms. HD5 kills microbes directly. HD6 does not kill directly but forms microscopic net-like mesh works (nanonets) that entrap the microbes, as do the extracellular traps that are released from dying neutrophils [96,97]. Evidence suggests that defective Paneth cells play a role in initiating inflammation in Crohn disease [107].

Human beta-defensins 1 to 6 (HBDs 1 to 6) are expressed on all epithelial surfaces, including those of the airways, urinary and gastrointestinal tracts, mouth, cornea and conjunctivae, and skin. Their production by epithelial cells can be constitutive (baseline, unstimulated) or inducible. Infectious or traumatic injury of epithelium elicits inflammatory cytokines that induce beta-defensin production [92,100,108]. Deficiency of HBD1 in sperm is associated with male infertility [109].

Cathelicidins are a family of AMPs widely distributed in nature. The human cathelicidin LL-37, the most thoroughly studied, is released from both neutrophils and epithelial cells. It exhibits a broad range of antimicrobial activities [93,95,110], neutralizes lipopolysaccharide (LPS), and plays a role in wound healing, angiogenesis, and clearance of dead cells. LL-37 is induced by vitamin D [111-113]. In both keratinocytes and macrophages, stimulation of toll-like receptor 2 (TLR2) results in the induction of the cytochrome P450 enzyme that converts vitamin D to its active form, which in turn induces the expression of LL-37. In this way, vitamin D can influence microbicidal defenses of both skin and circulating phagocytic cells [114]. This may explain, at least in part, why certain human infections (eg, tuberculosis) are more prevalent among populations with inadequate plasma levels of vitamin D, including those with more deeply pigmented skin [114]. (See "Vitamin D and extraskeletal health", section on 'Immune system'.)

Bacterial permeability-increasing protein (BPI) is expressed in neutrophil azurophilic granules and in oral, pulmonary, and gastrointestinal mucosal surfaces [115]. It selectively damages membranes of gram-negative bacteria and can opsonize the bacteria for phagocytosis by neutrophils. It has a high affinity for the lipid A region of LPS, which gives it the capacity to downregulate the effects of LPS on inflammation.

Epithelial and innate immune cells express other AMPs from several different structural classes across the body. Examples include:

C-terminal fragments of keratin released from corneal epithelial cells, which protect the cornea from infection, as do lysozyme, lactoferrin, and lipocalin in tears [116,117]

The bacteriostatic protein lipocalin 2 is secreted by alpha-intercalated cells in the collecting duct of the kidney, which also acidify the urine and defend against upper and lower urinary tract infection by binding uropathogenic Escherichia coli (E. coli) [118].

The glycoprotein uromodulin, the most abundant protein in human urine, forms filaments that bind to the pili of pathogenic bacteria, preventing their binding to urinary tract epithelium and allowing them to be flushed away with urine [119,120].

Hepcidin, a master regulator of iron metabolism that influences absorption and distribution of dietary iron. It has antimicrobial capacity against iron-dependent organisms such as malaria, tuberculosis, and human immunodeficiency virus-1 (HIV-1) [121-126].

Several chemokines, small chemotactic proteins that control migration of leukocytes into body tissues [127].

The existence of this broad repertoire of AMPs may in part explain the rarity of AMP resistance among pathogenic microbes. However, a second major function of these peptides is to govern the composition of the commensal micro-organisms that colonize our body surfaces. These species, which lack the attributes of major pathogens, can be relatively resistant to AMPs and thus may have had an evolutionary advantage over other microbes in adapting to this niche [90,93,128,129]. In fact, human gut microbes from all dominant species can resist even the high levels of AMPs secreted in response to inflammation [130].

Inherited variability in defensin gene expression has been reported to contribute to the risk of several diseases, including Crohn disease and psoriasis; and research suggests that AMPs play a part in the pathophysiology of other diseases, such as atopic dermatitis and necrotizing enterocolitis [92]. Neutrophils and saliva in children with Kostmann severe congenital neutropenia are deficient in defensins and LL-37. These children suffer life-threatening infections and severe periodontal disease. Granulocyte colony-stimulating factor administration corrects the neutropenia but not the periodontitis. Bone marrow transplantation restores salivary LL-37 and allows control of the periodontal disease [131]. (See "Congenital neutropenia", section on 'Severe congenital neutropenia'.)

Antibacterial oligosaccharides — A mother's milk protects her newborn against infection, at least in part through the antibodies and AMPs present in the milk. Human milk also contains oligosaccharides that have a direct antibacterial effect and a capacity to break down biofilms that bacteria use to protect themselves, thereby improving effectiveness of other antimicrobial agents [132].

Collectins — The collectins represent another type of secreted PRR (table 1). Collectins are collagen-like proteins that bind to carbohydrate or lipid moieties in microbial cell walls. They can have direct microbicidal activity or flag the microbial cell for recognition by the complement system and phagocytosis. They can promote uptake of cells that have undergone apoptosis (cell death without cell disintegration), particularly neutrophils: to avoid release of tissue-toxic constituents [133-138].

The first component of complement, the collectin C1q, is a circulating and cell-associated PRR. It fixes to antibody-coated micro-organisms, some unopsonized organisms, immune complexes, apoptotic cells, and damage-associated molecular patterns (DAMPS) to initiate the complement cascade and clearance of the organism or particle. But it is also involved in a broad array of physiologic functions beyond its role in the complement cascade, including a fundamental role in host defense and in preventing autoimmune disease, as demonstrated by the increased frequency of infections and systemic lupus erythematosus (SLE) in individuals who lack C1q [83,139-141]. (See "Complement pathways" and "Inherited disorders of the complement system".)

Mannose-binding lectin (MBL) is an antimicrobial lectin (carbohydrate-binding protein), a well-characterized collectin, and an acute-phase reactant produced by the liver [138,142]. MBL recognizes terminal mannose residues of carbohydrates on gram-positive and gram-negative bacteria, fungi, and some viruses and parasites. MBL can opsonize (from the Greek, to cater or prepare food for) microbes for phagocytosis and activate the complement pathway, leading to microbial cell lysis, chemoattraction of neutrophils, and phagocytosis. MBL deficiency is associated with frequent, relatively mild infections in children or immunocompromised adults.

Two of the four pulmonary surfactant proteins (SP-A and SP-D) are collectins that are found in a variety of tissues [143-146]. These proteins bind oligosaccharide PAMPs found on many gram-positive and gram-negative bacteria, viruses, and fungi [134-137,143]. SP-A is expressed in the placental amnion and amniotic fluid, where it may contribute to the amniotic anti-inflammatory response during pregnancy [137].

Lectins — Lectins bind carbohydrates. In the context of host defense, they bind to microbial carbohydrates. MBL is the prototypic host defense lectin, but ficolins 1, 2, and 3, and galectins are other important host defense lectins [147-152]. MBL and ficolins can bind directly to microbes and trigger antibody-independent activation of the lectin pathway, the third of the core pathways of complement activation (with the classical and alternative pathways). There are at least 15 members of the mammalian galectin family. Charcot-Leyden crystals, which characterize severe asthma and rhinosinusitis, are eosinophil-derived crystals of galectin-10 [153]. Some human galectins can bind directly to bacteria, disrupt their membranes, and kill them in the absence of complement. Galectins can inhibit replication of the influenza virus and induce apoptosis of certain cells [150,154,155]. Different galectin family members influence various stages of neutrophil biology, from extravasation, microbiocidal capacity, and neutrophil turnover. The last is achieved by upregulating surface phosphatidylserine, which promotes clearance by macrophages [156]. The lectin RegIII-gamma can kill gram-positive bacteria in the small intestines and has the special property of maintaining a thin zone that physically separates gut microbiota from the small intestinal epithelial surface [157,158].

Pentraxins — Pentraxins are a large family of proteins, highly conserved through evolution and characterized by a C-terminal pentraxin domain with five subunits [159-163]. C-reactive protein (CRP) and serum amyloid P (SAP) are the structurally short-arm family members. Pentraxin 3 (PTX3) is the prototypic "long pentraxin." CRP is an evolutionarily conserved protein and a classic acute-phase reactant, secreted in response to toll-like receptor (TLR) activation or proinflammatory cytokines [164]. It is the first PRR to be described, secreted by the liver, and named for its capacity to react with C-polysaccharide of pneumococci. It functions like an innate, rapidly responsive antibody in that it can fix C1q and activate the complement system, thereby promoting phagocytic clearance. CRP also promotes phagocytosis by directly binding immunoglobulin G (IgG) Fc-gamma receptors on phagocytes. PTX3, secreted particularly by macrophages and dendritic cells, can bind to endothelial surface P-selectin at sites of inflammation, which blocks neutrophil attachment and recruitment, thereby acting to diminish inflammation as infection is controlled [161]. Pentraxins also have the capacity, after binding C1q to trigger the complement cascade, to then interact with complement inhibitors to limit further fixation after fixation of the opsonin C3b [165]. SAP is a constituent of all human amyloid deposits, including those of amyloidosis and Alzheimer disease. Current therapeutic efforts focus on depleting SAP from tissues as a means of treating these two disorders [162]. (See "Acute phase reactants", section on 'Roles of CRP'.)

Cell-associated pattern recognition receptors — Membrane-bound pattern recognition receptors (PRRs) are expressed constitutively on many types of innate immune cells and on the professional (most active) antigen-presenting cells (macrophages, dendritic cells, monocytes, and B lymphocytes). On all of these cells, transmembrane signaling PRRs act as sentinels. Upon activation, they induce rapid upregulation of other PRRs.

The principal transmembrane and intracellular signal-transducing PRRs are summarized in the table and below (table 2) [166-172]:

Plasma membrane-bound and intracellular TLRs and their associated microbe detection-enhancing proteins (lipopolysaccharide [LPS]-binding protein, CD14, and MD-2).

C-type lectin receptors (dectins 1 and 2) and macrophage-inducible C-type lectin (MINCLE) on macrophages and dendritic cells.

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), termed NOD1 and 2.

RIG-1-like receptors (RLRs), termed RIG-1 (for retinoic acid-inducible gene 1), melanoma-associated differentiation protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2).

Toll-like receptors — Toll-like receptors (TLRs) are transmembrane PRRs that are found on and within cells of the innate immune system (particularly monocytes, macrophages, epithelial cells, and neutrophils), as well as dendritic cells and many other cell types [166-171]. TLRs recognize a variety of PAMPs and DAMPS, including microbial cell wall components, proteins, and nucleic acids (table 3). TLR signaling results in changes in the transcription factors that regulate a multitude of genes, including those encoding important proinflammatory cytokines. The Drosophila protein toll signals resistance to fungi in fruit flies and has a cytoplasmic signaling domain homologous with that of mammalian TLRs [173]. The sea urchin has 222 TLRs, illustrating the importance of these receptors to host defense throughout phylogeny [174]. (See "Toll-like receptors: Roles in disease and therapy".)

Ten human TLRs have been well defined; an 11th has been identified [175] (table 3). The first identified was TLR4, which is constitutively expressed on many human cell types. TLR4 is specific for and exquisitely sensitive to the presence of bacterial endotoxin (LPS) [176,177]. Picogram amounts of LPS (estimated to equal approximately 10 molecules per cell) are sufficient to stimulate immune cells [178]. The relative protection of the Indiana Amish farming community from asthma is driven by a long-term, low-level proinflammatory innate immune response mediated through TLRs [179,180].

TLRs are homologous with the mammalian interleukin-1 (IL-1) receptor [181], and they share a MyD88-dependent signaling pathway that induces the transcription factors NF-kappa-B (nuclear factor for the kappa-light chain enhancer in B cells) and activating protein-1 (AP-1). These factors transcribe the secretion of potent proinflammatory cytokines, including tumor necrosis factor (TNF), interleukin-6 (IL-6), and pro-IL-1-beta.

The central role of TLRs in host defense is demonstrated by experiments of nature in which genetic polymorphisms or mutations are associated with disease. Predisposition to serious viral infections illustrates this point:

Five of the 10 TLRs (TLRs 3, 4, 7, 8, and 9) can trigger production of the type-1 interferons (IFN-alpha, -beta, and -lambda) that are essential for antiviral immunity. Patients with deficiency of TLR3 [182], UNC93B (the TLR 3, 7, 8, 9 signaling molecule) [183], or STAT-1 (the signal transducer and activator of transcription-1) [184], have suffered severe viral infections, particularly herpes simplex virus-1 encephalitis [185]. (See "Toll-like receptors: Roles in disease and therapy", section on 'UNC93B1 deficiency, TLR3 mutations, TRIF deficiency, TRAF3 deficiency, and TBK1 deficiency'.)

Hepatocytes express PRRs, including TLRs 2, 3, and 4, and when challenged by pathogens, can deliver innate immune responses in the liver or by the acute-phase response systemically. Hepatocytes play a direct role in the innate defense against hepatitis C and hepatitis B viruses [186].

Polymorphisms in TLRs have been associated with impaired resistance to respiratory syncytial virus [187] and increased risk of invasive fungal infections [188]. In contrast, a polymorphism in TLR3 confers protection against HIV-1 infection [189].

TLRs are found on cells of both innate and adaptive immune systems, and although they play a fundamental role in host defense and anti-cancer immunity [190], they have also been reported to contribute to a variety of inflammation-associated pathologic conditions, including cancer, rheumatoid arthritis, psoriasis, diabetes, coronary heart disease, cardiac ischemia, transplant rejection, and asthma [191,192]. (See "Toll-like receptors: Roles in disease and therapy".)

Pattern recognition receptors linked to phagocytosis — Phagocytes express membrane-bound pattern recognition receptors (PRRs) on their cell surface, which often function in concert with the secreted PRRs. When these cell-surface PRRs bind PAMPs, they initiate phagocytosis, release of toxic oxidants, and delivery of pathogens to phagolysosomes filled with microbicidal products. In macrophages, pathogen-derived proteins are also processed into peptides and presented by cell surface major histocompatibility complex (MHC) molecules to engage and instruct antigen-specific T lymphocytes. (See "Antigen-presenting cells".)

The best studied PRRs found on macrophages include the following (table 2):

The macrophage mannose receptor recognizes carbohydrates with terminal mannan that are characteristic of a variety of microbes, especially fungi [138,193].

Certain members of the macrophage scavenger receptor family can bind bacterial cell walls and trigger phagocytic clearance of the bacteria [194-196].

Dectins-1 and 2 are transmembrane lectin receptors expressed on human macrophages, monocytes, neutrophils, eosinophils, dendritic cells, and lymphocytes [197-199]. Dectin-1 has binding specificity for beta-1,3-glucans, an important component of fungal cell walls. Mutations leading to deficient expression of dectin-1 have been reported in women with recurrent mucocutaneous fungal infections, particularly vulvovaginal candidiasis and onychomycosis [200]. Phagocytosis and killing of fungi by blood leukocytes from these individuals was normal, emphasizing the special role of dectin-1 in defense of skin and mucosa. An autosomal recessive mutation in caspase recruitment-containing domain 9 (CARD9), which is involved in signaling from dectin-1, has been associated with chronic mucocutaneous candidiasis [201]. (See "Chronic mucocutaneous candidiasis", section on 'Dectin-1 deficiency'.)

Another example of a membrane-bound PRR that promotes phagocytosis is the N-formylmethionine (N-fMet) receptor, which is expressed on neutrophils, monocytes, macrophages, and dendritic cells. The amino acid sequence N-fMet initiates all bacterial proteins but only mitochondrial proteins in mammalian cells [202]. Engagement of these bacterial structures by the N-fMet receptor on host immune cells chemoattracts these cells to the bacteria and activates them for phagocytosis and killing.

Intracellular pattern recognition receptors — Intracellular pattern recognition receptors (PRRs) include some of the TLRs, the NOD-like receptors, and the RIG-1-like receptor family (table 2).

TLRs 3, 7, 8, 9, and 10 reside inside the cell in endolysosomes, membrane-bound compartments that can contain bacterial breakdown products or viruses and digestive enzymes from fused lysosomes. These TLRs recognize nucleic acids derived from viruses and bacteria and stimulate the production of type 1 IFNs (alpha, beta, lambda) and proinflammatory cytokines. (See "Toll-like receptors: Roles in disease and therapy".)

Nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs) are intracellular PRRs that sense PAMPS and DAMPs. They are key components of the inflammasome, a multi-protein complex that activates the enzyme caspase-1, which then generates the active forms of the key proinflammatory cytokines IL-1 and IL-18 [203-206]. Caspase-1 protease activity also induces a lytic, proinflammatory form of cell death termed "pyroptosis" ("ptosis" in Greek denotes a falling, "pyro" in Greek is fire, highlighting the context of inflammation).

The relatively well-studied inflammasome components NOD1 and NOD2 recognize different structural core motifs of bacterial peptidoglycans [166,167,170-172,207]. NOD1 recognizes peptidoglycan of all gram-negative bacteria and certain gram-positive bacteria. NOD2 recognizes muramyl dipeptide, a peptidoglycan motif present in all gram-positive and gram-negative bacteria [166,170,207-209]. NOD2 is expressed in monocytes, macrophages, dendritic cells, lymphocytes, epithelial and endothelial cells, and intestinal Paneth cells. TNF-alpha and IFN-gamma can upregulate the NOD2 gene in intestinal epithelial cells [210]. Engagement of either NOD1 or NOD2 activates the transcription factor NF-kappa-B, which results in upregulated transcription and production of the proinflammatory mediators. NOD2 has been of particular interest in Crohn disease, because three polymorphisms in the NOD2 gene are associated with a 2- to 4-fold risk of this disorder in heterozygotes and an 11- to 27-fold risk in homozygotes [211-213]. (See "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease", section on 'Immune dysregulation and IBD'.)

The RIG-1-like receptor family (RIG-1, MDA5, and LPG2) is a second family of cytoplasmic PRRs. These PRRs recognize the RNA of internalized viruses and mediate production of type-1 IFNs and antiviral immune responses [166,167,171,214].

Genetic defects of PRRs are variable in severity, have a narrow specificity for particular classes of pathogens, and often decrease in severity with age [215].

CELLS OF THE INNATE IMMUNE SYSTEM — "Professional" phagocytes (neutrophils, monocytes, macrophages) represent the critical effector component of the innate immune system [216-218]. Other cell types, including epithelial cells, eosinophils, mast cells, and platelets, express pattern recognition receptors (PRRs), including toll-like receptors (TLRs), and play an important contributory role in innate host defense. Dendritic cells express PRRs, and as principal antigen-presenting cells, they serve to link innate and adaptive immunity [219,220]. Mechanisms by which these cell types influence immune homeostasis and the adaptive immune response are discussed separately. (See 'Homeostasis in the innate immune system' below and 'Innate immunity instructs adaptive immunity' below.)

Neutrophils — Neutrophils, the most abundant circulating phagocytes in humans, are the first cells recruited into sites of infection and inflammation [221]. They are attracted by four major chemotactic factors generated at these sites, and there are specific neutrophil receptors for each. These factors are N-formyl bacterial oligopeptide, complement-derived C5a, leukotriene B4 (secreted by numerous immune cells), and the neutrophil chemokine interleukin-8 (IL-8), which is secreted by activated innate immune cells and epithelial cells. Certain antimicrobial peptides (AMPs) are also chemotactic for neutrophils [222]. All of these chemoattractants diffuse from the site of infection or injury to provide a chemotactic gradient for neutrophil migration and to further activate neutrophils as they transmigrate. (See "Leukocyte-endothelial adhesion in the pathogenesis of inflammation" and "Laboratory evaluation of neutrophil disorders" and "Approach to the adult with unexplained neutropenia" and "Approach to the patient with neutrophilia" and "Approach to the patient with neutrophilia", section on 'Causes of neutrophilia'.)

Upon reaching the infected site, neutrophils phagocytose invading micro-organisms that have been prepared for phagocytosis (opsonized) by innate and acquired immune processes, such as fixation of complement C3 fragments and immunoglobulin G (IgG). Complement receptors 1 and 3 (CR1 and CR3) are the main phagocytic receptors for opsonic C3 fragments [147]. In the presence of antibody to cancer antigens, neutrophils, as well as natural killer (NK) cells and macrophages, can lyse the cancer cell by antibody-dependent cellular cytotoxicity [223]. (See "Complement pathways".)

Following phagocytosis, microbicidal mechanisms kill the ingested microbes almost immediately by merging the microbe-containing phagosome with intracellular granules containing microbicidal products, such as alpha-defensins and highly reactive oxidants generated by the phagocyte NADPH oxidase (O2-, H2O2, hypochlorous acid, hydroxyl radical) [216,224]. Phagocyte NADPH oxidase has an essential role in killing certain common organisms (eg, staphylococci, enteric bacteria, and Aspergillus), as evidenced by the prominence of infections by these organisms in chronic granulomatous disease (CGD), in which the phagocyte oxidase is deficient [225]. (See "Primary disorders of phagocyte number and/or function: An overview" and "Chronic granulomatous disease: Pathogenesis, clinical manifestations, and diagnosis" and "Neutrophil-specific granule deficiency".)

Neutrophil cytoplasmic granule proteases (neutrophil elastase and cathepsin G) are also important to neutrophil microbicidal function. These cationic proteases, rendered inactive in resting cells by component proteoglycans, are solubilized and activated by the conditions in phagocytic vacuoles [226]. Thus, maximal toxicity of these proteases is confined to phagocytic vacuoles, and damage to host tissues is limited. A number of neutrophil subsets with different phenotypic properties have been described [227].

As neutrophils crawl toward microbial targets, they release extracellular strands of chromatin decorated with antimicrobial proteins. These neutrophil extracellular traps (NETs) capture and kill microbes and prevent collateral damage by localizing proteases and degrading cytokines and chemokines [228-235]. NETs interact directly with the coagulation system to induce clot formation that can further trap pathogens [236,237]. Mucins and lysozyme in saliva exert antibacterial activity [238], and salivary mucins stimulate release of antimicrobial NETs from salivary neutrophils [233,234]. Saliva from Behçet disease patients, who suffer recurrent oral ulcers, did not induce NET formation [233,234]. Macrophages can clear NETs, but when NETs are elicited by cholesterol crystals, which characterize atherosclerotic plaques, NETs prime the macrophages to release cytokines that drive inflammation [239].

There is evidence to suggest that NET formation can predispose to autoimmune and vasculitic diseases, including rheumatoid arthritis and systemic lupus erythematosus (SLE), as well as diabetes, atherosclerosis, Alzheimer disease, COVID-19 immunothrombosis, muscle damage-induced kidney dysfunction, sepsis injury, and even cancer [81,240-251].

Other components of the neutrophil's potent antimicrobial armamentarium are proinflammatory and can participate in tissue damage when the stimulus is an immune complex or collagen vascular disease or the contents of an arteriosclerotic plaque [252]. Homeostatic balance is restored by tissue DNases that break up the core DNA of the NET [253,254].

Neutrophils are not end-stage cells incapable of modification after leaving the bone marrow, as had been originally thought. Their antimicrobial functions can be markedly upregulated by bacterial products [11], and certain neutrophil populations can return to the circulation or migrate into lymph nodes following their initial extravasation [227]. These functions may facilitate inflammation or antigen presentation, respectively.

Monocytes and macrophages — Monocytes develop in the bone marrow and circulate before infiltrating tissues where they differentiate into either macrophages or dendritic cells [255]. Some pick up antigens and transport them to regional lymph nodes without becoming macrophages [256]. Most serve to renew the resident macrophage population while differentiating into macrophages that are characteristic for the tissue in which they reside (eg, interstitial and alveolar macrophages in the lung, Kupffer cells in the liver, osteoclasts in bone, cardiac macrophages [257,258], and microglia in the brain and retina) [259-265]. This process is accentuated in response to infection or cancer [266-269]. Tissue resident macrophages also arise from yolk sac/fetal liver embryonic progenitors independently of blood monocytes. These and the progeny of monocyte infiltration can self-renew [259-261,266,270]. The generation of foam cells in atherosclerotic plaques results primarily from macrophage proliferation within the plaques [271,272]. It appears that all of these tissue macrophage populations can differentiate into either proinflammatory, microbicidal (M1), or anti-inflammatory, pro-healing (M2) subtypes [266,273].

Multinucleated giant cells formed by fusion of macrophages retain their ability to phagocytose and express the metabolic and antimicrobial properties of macrophages [274,275].

Macrophages express a high density of surface PRRs, and like neutrophils, they respond rapidly to the presence of microbes. These two cell types complement each other and cooperate in effecting innate immunity [217], but they differ in several important ways. Among these, macrophages have an important role in digesting microbes and presenting microbial antigens to lymphocytes to initiate an adaptive immune response to the microbe. In addition, macrophages secrete over 100 proteins that mediate host defense and inflammation, including potent cytokines. They also play an essential role in systemic iron homeostasis, supplying iron for erythropoiesis or sequestering it to prevent iron-dependent bacterial growth [276].

Inflammation is the classic "double-edged sword," however, and macrophages cut both ways. Central nervous system microglia illustrate this point. These cells evolved to mediate neuronal development [277,278] and to protect the brain from microbial assault, but immune activation in which microglia are key perpetrators is a common feature of neurodegenerative diseases, including Alzheimer and Parkinson diseases, viral encephalopathy, stroke, traumatic brain injury, and multiple sclerosis [261,279-284]. Disorders associated with monocytosis or with excessive activation of macrophages are discussed elsewhere. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Eosinophils — Eosinophils release extracellular traps carrying attached eosinophil granules that secrete their contents when stimulated [285,286], and they possess a well-known role in resisting parasitic infection. They are also recognized to be multifunctional cells that have antibacterial and antiviral activity [287]. Eosinophils circulate but they are primarily resident in the lamina propria of the gastrointestinal tract. They are nurtured there and throughout the body by interleukin-5 (IL-5), interleukin-13 (IL-13), and cytokines from immune cells. Unfortunately, their intestinal location allows them to mediate the eosinophilic gastrointestinal diseases (EGIDs) (eosinophilic esophagitis [most common], gastritis, enteritis, and colitis) and inflammatory bowel diseases [287-292]. In addition, eosinophils and platelets can interact to promote atherosclerotic plaque formation and thrombosis [286].

Basophils — Basophils are leukocytes of myeloid origin that appear only in blood. They express immunoglobulin E (IgE) receptors and are thus primed to participate in the allergic response and resistance to helminth infestation upon release of histamine, cathelicidin, and other mediators. These include IL-4 and IL-13, which promote a lymphocyte T helper type 2 (Th2) response, further enhancing the allergic and antihelminthic response and promoting B cell production of antibody [293].

Mast cells — Mast cells reside in large numbers in the interstitium of peripheral tissues. They express TLRs 1, 2, 4, and 6, receptors for the complement "anaphylatoxin" C5a, and receptors for mannose-binding lectin (MBL). Upon PRR activation, mast cells release tumor necrosis factor-alpha (TNF-alpha) and IL-8, which are uniquely preformed in mast cells. Mast cells also make classic inflammatory mediators (histamine, heparin, leukotrienes, platelet-activating factor), proteases (eg, tryptase, chymase), and AMPs (cathelicidin and defensins) [294-298]. They have immunomodulatory as well as antimicrobial and anti-protozoan functions; and they promote bone metabolism [297-301]. (See "Mast cells: Development, identification, and physiologic roles" and "Mast cells: Surface receptors and signal transduction" and "Mast cell-derived mediators".)

Natural killer (NK) cells — NK cells are an innate immune cell type with unique features. They are lymphoid cells that do not express antigen-specific receptors derived from exposure to specific antigens, such as T cell receptors or surface immunoglobulin on B cells. However, NK cells can alter their behavior based on prior exposure to particular antigens, including after viral infection, by a mechanism that is different from that of T and B cells [302-308].

NK cells express a broad array of activating and inhibitory receptors, including TLRs 2, 3, 4, 5, 7, and 8, and they recognize and respond to the respective TLR ligands directly [304,309,310]. Activating receptors are central to the "killer" function of this cell type, which is to respond to viral infections (especially herpesvirus infections) and malignant tumors by recognizing damaged or "stressed" host cells for elimination. NK cells have granules with perforins and granzymes that, upon activation, are released into the interface between target and effector NK cells, disrupting target cell membranes and inducing apoptosis [311]. NK cells distinguish and avoid healthy host cells through receptors that recognize major histocompatibility complex (MHC) class I molecules expressed on all normal healthy cells [312]. Binding of these receptors inhibits NK cell-mediated lysis and cytokine secretion, whereas deficiency or absence of surface MHC I will target that cell for attack. Since virus-infected and malignant cells often downregulate MHC class I molecules, they become susceptible to attack by NK cells [304,313]. The inhibitory receptors on NK cells are counterbalanced by activating receptors that recognize "stress" ligands expressed on cell surfaces in response to intracellular DNA damage [304].

In the give and take between the host and an infecting virus [314], NK cells play a central role, as shown by the serious herpesvirus infections sustained by an adolescent lacking NK cells [315]. NK cells are reduced in number, metabolically stressed, and functionally deficient in obese children, which could relate to the increased rates of cancer in this population [316]. The "immunosenescence" that occurs with aging is regularly associated with a decrease in the number and function of NK cells. Exercise has been experimentally shown to increase the number and cytolytic capacity of NK cells in this population [317]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis", section on 'Biology of NK cells'.)

Three risk factors have been identified for COVID-19: being male or elderly or having an underlying medical condition. However, within other demographic groups, there is large variability in susceptibility to severe COVID-19. Secretion of type 1 interferons, IFNs alpha and beta being the prototypes, is central to the antiviral capacity of NK cells. At least some of the variability in severity of COVID-19 can be explained by genetic variants or autoantibodies that result in deficient release of type 1 interferons [318-321]. (See "Toll-like receptors: Roles in disease and therapy", section on 'Severe COVID-19'.)

Epithelial cells — Epithelial cells function as tissue-based sentinels. Like macrophages, these cells reside in tissue areas of high antigenic exposure and express PRRs that allow them to recognize pathogen-associated molecular patterns (PAMPs) and respond even more quickly than neutrophils and monocytes do. Epithelial cells provide a continuous physical barrier, as well as clearance mechanisms (eg, mucociliary system and surfaces coated with AMPs) to protect the host from the external environment. Human airway epithelial cells express multiple TLRs and when PAMP-stimulated, produce proinflammatory cytokines, including interleukin-8 (IL-8) [322] and AMPs [323]. Human skin keratinocytes express a mannose-binding receptor that mediates killing of candida [324], and they release multiple AMPs [325]. Paneth cells, specialized epithelial cells at the base of intestinal crypts, secrete lysozyme and other AMPs during intestinal infection [326]. In the gastrointestinal tract, TLR-mediated epithelial responses to the PAMPS of commensal bacteria promote epithelial integrity and resilience to injury [327]. Signaling through TLRs on amniotic epithelial cells leads to release of cytokines that could provoke preterm labor [328].

Tuft cells — Bitter taste receptors in the upper respiratory tract can protect against toxic compounds, including bacterial products from spoiled food. They also protect against infection by responding to bacterial products with vigorous release of AMPs [329]. Tuft cells are specialized epithelial cells in the linings of the intestines, lungs, nasal passages, pancreas, gallbladder, thymus, and urethra. They display taste receptors in most locations. These cells serve as innate sentinels along the body's invasion routes that detect pathogens and allergens and help coordinate antimicrobial responses, with a particularly important role in rejecting parasites [330,331].  

Platelets — Platelets are well known for their role in hemostasis, but they also play a remarkable role in host defense, wound repair, and resolution of the inflammatory process [332-340]. They express PRRs, produce cytokines, recruit leukocytes to sites of infection or tissue damage, and interact with leukocytes and endothelial cells through P-selectin to mediate proinflammatory events [332,341], including the killing of malaria parasites and staphylococci [334,335,342]. Like other components of the inflammatory process, however, their roles in mediating inflammation involve them in pathologic conditions, such as atherosclerosis and sepsis syndrome [336,337,343,344].

Megakaryocytes, from which platelets bud off, secrete IFNs alpha and beta and express intrinsic antiviral immunity [345,346].

Innate lymphoid cells — Innate lymphoid cells (ILCs, groups 1 to 3) are a diverse group of lymphocytes found in many tissues, particularly the skin and the mucosal barriers of the lungs and gastrointestinal tract. They develop from the common lymphoid progenitor but do not express antigen receptors or expand into a clone when stimulated [347-352]. Instead, they react quickly to signals from infected or injured tissues by releasing an array of cytokines, including interferon-gamma (IFN-gamma), interleukin-5 (IL-5), and interleukin-17 (IL-17), which direct the immune response to the source of ILC stimulation [353]. Some have cytolytic potential and can directly kill tumor cells [354,355]. They limit T cell adaptive responses to intestinal commensal bacteria [356], continuously produce IL-5 which regulates eosinophil homeostasis [357], and promote glycosylation of the intestinal epithelial cell surface, which is required to allow survival of the gut microflora but prevent their invasion [358]. At least in mice, ILCs also protect against C. difficile infection [359]. Genetic impairment of ILC3 function may be involved in the pathogenesis of Crohn disease [349,360].

Dendritic cells — Dendritic cells, the major antigen-presenting cells, begin life in an unprogrammed, innate state but serve an essential role in adaptive immunity and represent a key link between the innate and adaptive systems [263,361-365]. Dendritic cells express branched (dendritic) extensions and endocytic capacity but are heterogeneous from the standpoint of location, surface markers, and level of antigen-presenting activity [263]. As they mature, they develop antigen specificity and thus become an essential component of the adaptive immune system. Dendritic cells capture, process, and present antigens to unprogrammed T cells in order to induce adaptive immunity or tolerance to self-antigens. The functions of dendritic cells and other antigen-presenting cells are reviewed in more detail elsewhere. (See "Antigen-presenting cells".)

The mechanism by which endotoxin and other PAMPs enhance the adaptive immune response to antigen involves the potent induction of interleukin-12 (IL-12) and type 1 interferons (IFNs) alpha and beta by the antigen-presenting cells, dendritic cells, and macrophages [366,367]. These mediators are key regulators of dendritic cell development and the T-helper type 1 (Th1) immune response that is essential to host defense.

Dendritic cells that have migrated into lymphoid organs and peripheral sites of the dendritic cell network internalize microbial products (lipopolysaccharide [LPS] and other PAMPs that bind to PRRs), molecules released from damaged tissue (DAMPs, "danger signals" or "alarmins"), some tumors, or self-antigens [368,369]. This "innate" step induces dendritic cell maturation, which is accompanied by upregulation of cytokine receptors, the major histocompatibility complex (MHC) class II, and the costimulatory molecules CD80 and CD86. Dendritic cell subtypes express different PRRs, but all possess various TLRs [370]. Once matured, dendritic cells present antigen to unprogrammed T lymphocytes and induce their proliferation. These effector T lymphocytes actively secrete IFN-gamma, which in a positive feedback relationship, further primes the dendritic cells to produce greater amounts of IL-12 in response to stimulation [371,372]. IFN-gamma also activates macrophages to a more effective microbicidal state. Defects in the IFN-gamma/IL-12 mechanism resulting in immunodeficiency are discussed separately. (See "Mendelian susceptibility to mycobacterial diseases: Specific defects".)

Adipocytes — Adipocytes (fat cells) in lean tissue act as a dynamic endocrine organ that secretes adipokines to coordinate the intake, utilization, and storage of nutrients [373]. Leukocytes that traffic to and reside in lean adipose tissue are believed to contribute to this control [374,375]. Adipocytes in obese visceral tissue are enlarged, and their associated immune cells release proinflammatory mediators, including TNF-alpha, IFN-gamma, and IL-1, which are believed to inhibit insulin action and promote metabolic syndrome, type 2 diabetes, and cardiovascular disease [374-378]. However, adipocytes also participate in host defense. In a mouse model, S. aureus skin infection induced prominent expansion of the dermal adipose layer, at least in part due to hypertrophy of individual adipocytes [379-381]. These cells produce the AMP cathelicidin, which kills the staphylococci [379].

HOMEOSTASIS IN THE INNATE IMMUNE SYSTEM — Although humans exist day-to-day in a hostile microbe-laden environment, we are normally unaware of the constant battles waged to prevent harmful infection. For those with a normal immune system, signs of infection-induced inflammation are relatively uncommon, and when they appear, they disappear as soon as the battle is over. This potent but unapparent immune protection of the well-defended host is a reflection of the quiet efficiency of front-line defenses (eg, antimicrobial peptides [AMPs], complement, and phagocytes) combined with active homeostatic processes within the innate immune system that regulate and limit inflammatory responses. In sum, microbe-induced activation of the innate immune system is tightly linked to the concurrent induction of downregulatory mechanisms to regain immune homeostasis. A few examples illustrate this point:

Macrophages are essential for host defense, but they also play a central role in maintaining immune homeostasis. For example, engagement of pathogen-associated molecular patterns (PAMPs) with macrophage pattern recognition receptors (PRRs) primes pulmonary alveolar macrophages for antimicrobial activity, but as the infection clears, these cells actively suppress dendritic cell maturation, antigen presentation, and function in adaptive immunity [382-384]. Activation of macrophages induces not only proinflammatory antimicrobial responses but also the anti-inflammatory mediators, interleukin-10 (IL-10), transforming growth factor-beta (TGF-beta), and prostaglandin E2 (PGE2), which downregulate macrophage and dendritic cell functions.

There appear to be subtypes of neutrophils [385]. One of these promotes vascularization [386,387] and another inhibits T cell responses [388].

Eosinophils contribute to tissue remodeling and repair [389], induction of dendritic cell activation and adaptive immunity, maintenance of immunoglobulin A (IgA)-expressing plasma cells, and other regulatory functions [390].

During the early stages of inflammation, endothelial cells and neutrophils release specialized proresolving mediators (resolvins, protectins, and maresins), which enhance clearance of bacteria and apoptotic/necrotic cells, decrease release of macrophage pro-inflammatory cytokines, accelerate clearance of acute inflammation, and suppress tumor growth [391,392]. The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are substrates for synthesis of these agents through a process involving cyclooxygenase 2 (COX-2) [393-398]. COX-2 inhibitors, such as celecoxib, inhibit release of resolvins, perhaps explaining in part the deleterious effect of COX-2 inhibitors in acute infectious inflammation, and over time, cardiovascular disease. In contrast, atorvastatin promotes synthesis of resolvins, which could play a role in the anti-inflammatory effect of statins [393,399,400]. EPA and DHA from fish oil displace membrane arachidonic acid, the source of bronco-constrictive leukotrienes. Mothers given fish oil in the third trimester delivered offspring who had one-third the rate of persistent wheezing or asthma over a five-year period compared with offspring of a control group given olive oil [401-404].

Efferocytosis — Efferocytosis (Latin for "to take to the grave" or "to bury") is a remarkable example of homeostasis within the innate immune system. The term refers to the uptake and processing of apoptotic (dead but relatively intact) cells by macrophages and dendritic cells [405-407]. In a normal adult, about 100 billion neutrophils leave the marrow, circulate, enter tissues, and die each day, even in the absence of acute infection [408]. Cells become senescent and die in all tissues, particularly as the body ages [409,410]. Apoptotic cells and autolyzed, necrotic neutrophils release cytotoxic, proinflammatory constituents (DAMPs) into their environment unless countered by this constitutive anti-inflammatory process of apoptotic cell recognition and ingestion. The constant turnover of dying cells, particularly neutrophils, would be potently inflammatory without the process of efferocytosis. Phagocytic removal of apoptotic cells prevents release of their toxic constituents by necrosis, thereby reducing the risk of autoimmunity. Moreover, this process shifts macrophage and epithelial cell cytokine release from proinflammatory to anti-inflammatory, further moving the process toward resolution [396,411-415]. Thus, efferocytosis is central to the successful resolution of inflammation [406,413,414,416,417]. As humans age, efferocytosis becomes less efficient, resulting in persistent inflammation and decreased resistance to infection [409,410]. Although macrophages have received most of the attention in mediating efferocytosis, other cell types can perform the same function, including epithelial and endothelial cells, fibroblasts, and stromal cells.

Macrophages recognize apoptotic cells through molecular patterns, reminiscent of microbial recognition by innate immune cells. The plasma membrane of viable cells actively maintains an asymmetric phospholipid distribution such that phosphatidylserine is kept on the inner side of the membrane bilayer. Apoptosis perturbs this asymmetry and exposes phosphatidylserine on the cell's outer surface, leading to its recognition by macrophages bearing phosphatidylserine receptors [418-420]. Upon recognition of apoptotic cells, macrophages release anti-inflammatory IL-10, PGE2, and TGF-beta to complete the task of maintaining immune homeostasis. In turn, the apoptotic process in monocytes and macrophages themselves is regulated by a complex network of differentiation factors and inflammatory stimuli that determine their lifespan and thus their participation in the yin-yang of host defense [421].

The pathogenicity of some bacteria depends on their release of cytotoxins that induce phagocyte necrosis and temporarily overwhelm efferocytosis [422]. High mobility group box 1 (HMGB1), a DNA-binding nuclear protein released from disrupted cells, is a potent mediator of inflammation through its capacity to diminish phagocytic uptake of apoptotic cells [423].

Clearance of necrotic cells and cell debris involves some of the same "find-me" and "eat me" signals and phagocytic cell receptors central to removal of apoptotic cells; but the process differs in other important ways, including the signals and receptors employed [424]. The complement component C1q and the collectins, mannose-binding lectin (MBL) and surfactant proteins (SP-A and SP-D), can bind apoptotic and necrotic cells and mediate their clearance [424,425]. Individuals with genetic C1q deficiency commonly present with autoimmunity, which is hypothesized to be due at least partly to deficient phagocytic clearance of apoptotic cells [424,426,427]. (See "Inherited disorders of the complement system", section on 'C1 deficiency'.)

Defects in immune homeostasis — Individuals with chronic granulomatous disease (CGD) suffer severe bacterial and fungal infections but also various inflammatory disorders, such as sterile inflammation and inflammatory bowel disease [428,429]. This apparently contradictory combination of problems has been attributed to the dual functions of NADPH oxidase, which is defective in the neutrophils and macrophages of patients with this disease. Infections result from defective NADPH oxidase-dependent, phagocytosis-associated generation of microbicidal oxygen metabolites, such as hydrogen peroxide. Excessive inflammation is attributed to a defect in the regulation of inflammation by NADPH oxidase, and studies with murine and human CGD phagocytes show failure during phagocytosis to activate nuclear factor erythroid 2-related factor 2 (Nrf2), a key redox-sensitive anti-inflammatory regulator [430]. In addition, CGD macrophages do not ingest apoptotic neutrophils normally [431]. This can be reversed by exposure of the macrophages to the key macrophage activator interferon-gamma (IFN-gamma), which is used in the treatment of CGD [432]. (See "Chronic granulomatous disease: Treatment and prognosis".)

INTERACTION OF INNATE AND ADAPTIVE IMMUNITY — When the concept of innate immunity was initially developed, the emphasis was on the emergence of certain immune mechanisms early in evolution and how these mechanisms function without needing prior experience with the microbe or the help of T or B lymphocytes. However, as the field progressed, pattern recognition receptors (PRRs) were recognized on cells of the adaptive system as well, demonstrating that the innate and adaptive immune systems interact at many points and enhance each other's function [433-436].

Innate immunity instructs adaptive immunity — The adaptive immune system has a potentially limitless repertoire of antigen receptors, but innate mechanisms help to focus adaptive responses on pathogens rather than on harmless environmental antigens or self-antigens. Examples include the following:

Role of pattern recognition receptors — The interaction between pathogen-associated molecular patterns (PAMPs) PRRs is central to the function of the innate immune system, but it also controls the activation of adaptive immune responses by directing microbial antigens through the cellular processes that lead to presentation to T and B lymphocytes [191,192,433-439].

Endotoxin (lipopolysaccharide [LPS]), a PAMP that makes up most of the outer membrane of gram-negative bacteria, is a powerful adjuvant in the induction of antigen-specific T cell memory [434,435,437]. Specifically, vaccination with protein antigen alone results in a short-lived proliferative response of B and T lymphocytes. However, a very different response ensues if endotoxin is included with the antigen, which more accurately reflects the way the human body would encounter most microbial antigens in nature. Including adjuvant with a vaccine results in a long-lived response from effector T cells, a persistent antibody response, and the development of immunologic memory [438,439]. Protection against whooping cough by the acellular pertussis vaccine is proving to be shorter-lived than that of whole cell vaccine, which contained large amounts of endotoxin. At least with some antigens, collaboration between the innate and adaptive systems gives the optimally protective immune response.

Innate immune PRRs, particularly TLR2 and TLR4, also recognize and expedite the removal of damage-associated molecular patterns (DAMPs) or "alarmins" that are released from host cells as a result of infection or tissue injury (see 'Damage-associated molecular patterns (DAMPs)' above). Once released extracellularly, alarmins can activate innate immune cells to release proinflammatory cytokines that can lead to shock, organ failure, and sepsis syndrome [81,82,369,440,441]. Complicating the management of these life-threatening clinical conditions, a compensatory anti-inflammatory response syndrome (CARS) occurs alongside the proinflammatory response, blunting the host defense capacity of the innate immune system [442,443]. When the compensatory response is severe, "immunoparalysis" occurs, affecting both innate and adaptive immunity [444]. Alarmins can enhance the adaptive immune response, however, through their stimulation of dendritic cells, thus serving to link innate immunity to the adaptive arm of the immune response.

Role of innate immune cells — Neutrophils, macrophages, natural killer (NK) cells, and other cells of the innate immune system feature PRRs that recognize microbial antigens and stimulate a direct antimicrobial response. But these cells also promote antigen-specific adaptive immunity through various means as they work to directly eliminate invaders. (See 'Cells of the innate immune system' above.)

Dendritic cells function as a direct link between innate and adaptive immunity, with the capacity to ingest foreign antigens through PRRs and then to process and present their products to T and B lymphocytes. (See 'Dendritic cells' above.)

Innate immune NK cells, macrophages, and dendritic cells contribute to direct control of viral replication and induce viral-specific adaptive immune responses (antibody and cytotoxic T cells). For example, influenza virus initiates rapid differentiation of monocytes into dendritic cells that produce interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta), which in turn contribute to the innate antiviral response [445].

Neutrophils can form networks with dendritic cells and NK cells that upregulate NK cell release of IFN-gamma [446], which can then activate macrophages and thereby enhance T cell-dependent, cell-mediated immunity. Although studies suggest that a subset of neutrophils can inhibit T cell responses [388], neutrophil extracellular traps (NETs) can prime T cells so that they respond more effectively in antigen processing [447].

Role of antimicrobial proteins and peptides — Antimicrobial proteins and peptides (AMPs) protect the skin and mucosal surfaces and participate in the killing of phagocytosed organisms (see 'Antimicrobial peptides' above). Beyond this first-line, rapid-response function, these molecules support the development of an adaptive immune response to the threatening organisms in several ways [448-452]:

AMPs serve as chemoattractants for adaptive immune cells, as well as for neutrophils and monocytes. Recruitment of dendritic cells by AMPs induces their maturation. Human alpha-defensins attract immature dendritic cells and peripheral blood CD4 and CD8 T cells, thereby enhancing antigen-specific adaptive immune responses [448].

Human beta-defensin-2 can enhance IFN-gamma release from blood T cells [449].

In vitro studies show that human LL-37 stimulates dendritic cells to express increased endocytic capacity, modified phagocytic receptor function, upregulation of costimulatory molecules, enhanced secretion of T helper type 1 (Th1)-inducing cytokines, and enhanced Th1 responses [450].

The beta-defensins and LL-37 are chemoattractive for mast cells and can induce their degranulation [451,452]. Mediators in mast cell granules can affect adaptive immunity by modifying dendritic cell function [453]. (See "Mast cells: Development, identification, and physiologic roles", section on 'Innate immunity'.)

Adaptive immunity enhances innate immunity

Amplification of host defense also goes in the direction of adaptive to innate. Dendritic cells recruit, interact with, and activate NK cells through cytokines (eg, type I IFNs, IL-12, IL-18) and cell-to-cell surface interactions [304,454,455].

Opsonization of encapsulated bacteria by complement fragments facilitates phagocytosis by cells bearing complement receptors, such as neutrophils and mononuclear phagocytes. However, even in the presence of a fully active innate complement system, clearance of heavily encapsulated bacteria, such as pneumococci, is ineffective in the absence of antibody, as evidenced by the clinical course of individuals with hypogammaglobulinemia. (See "Complement pathways", section on 'Biologic functions of complement'.)

Macrophages can ingest mycobacteria during their first encounter, but they cannot kill them effectively unless activated by IFN-gamma, a cytokine released from T cells that have been programmed by exposure to mycobacterial antigens.

INTEGRATION OF INNATE IMMUNITY INTO OTHER PHYSIOLOGIC SYSTEMS — Survival against infection was a major driver of evolution. As organ-specific and general body systems of human physiology evolved, many incorporated innate host defense elements to protect against infection. Examples are described below.

Integration with nervous system functions — Both clinicians and the general public have long recognized that mental and physical health are interrelated in what is commonly referred to as the "mind-body connection." Research has indicated emotional health and a positive emotional style favor cardiovascular health, accelerated recovery from infection, and resistance to colds and to respiratory infection after controlled nasal inoculation of rhinovirus or influenza virus [456,457].

The central nervous system (CNS) and the immune system had been thought to act independently until recently. It is now clear that there is highly organized communication between the two systems that preserves homeostasis in health and disease [458,459]. The CNS communicates with the immune system through hormonal and neural pathways (sympathetic, parasympathetic, and enteric). The immune system influences the CNS through cytokines from activated immune cells in the periphery and activated microglia and astrocytes in the spinal cord and brain [460,461]. Neuro-immune crosstalk plays a key role in the pathophysiology of allergic disease and asthma [462].

Stimulation of the brain's reward system in mice resulted in upregulation of innate immune cell receptors, including toll-like receptor 4 (TLR4), increased phagocytosis and killing of E. coli by macrophages, and an increased adaptive immune response [463,464]. The reward system's effects were mediated at least partially by the sympathetic nervous system, which extends from the brain into the spleen and other lymphoid organs. These responses to a perceived reward may also play a part in the placebo effect.

The efferent vagal pathway of the central nervous system connects with acetylcholine receptors on immune cells in the spleen and liver, suppressing cytokine release and inflammation [465-467]. This and other examples of the neuronal inflammatory reflex illustrate the central and essential role that neuronal signals play in regulating the immune response [467]. In fact, each of the four classic signs of inflammation, dolor (pain), calor (heat), tumor (swelling), and rubor (redness), are primarily due to neuronal activation.

The complement system and microglia, the brain's macrophages, are active in brain host defense and in clearing debris and promoting healing after traumatic brain injury [468,469]. Microglia are also essential to normal brain development, because they prune weakly active, unnecessary synapses to allow more active synapses to develop during normal brain maturation. This pruning process is guided by tagging of the superfluous synapses by C1q and the complement system. Microglia then phagocytose tagged synapses through their complement receptors [470]. Recent data indicate that during development microglia orchestrate construction and regulation of neural networks in the adult brain [277,278].

Not unexpectedly, however, microglia and complement can play a central role in brain disease, including autism and Alzheimer disease [471]. As humans age, brain C1q levels rise dramatically, and these may drive neurodegenerative disease and cognitive decline through the complement recognition mechanism [472]. Serum C1q levels also rise steeply with aging as a reflection of muscle loss; levels can be returned to baseline by a program of resistance exercise [473], raising the interesting possibility that resistance exercise could reduce unwanted inflammation by reducing available C1q. At least in mice, complement-dependent synapse elimination by microglia underlies the normal forgetting of remote memories [474,475]. Some individuals with heritable schizophrenia have greater expression in the brain of complement component C4A, perhaps explaining the cortical thinning and reduced numbers of synaptic structures characteristic of this disorder [476,477].

Variation in expression of innate immune components in the cerebellum and cerebral cortex, brain areas that evolved separately, appears to permit infection by herpes simplex virus specifically in the cortex and infection by West Nile virus in the cerebellum [478].

Substance P is a peptide neurotransmitter secreted by sensory neurons. Its receptor is distributed over many cell types and tissues, and it can modulate immune cell proliferation, cytokine release, and inflammation. It shares physical and chemical properties with AMPs and has direct antimicrobial activity [479,480].

A systematic review and metanalysis of 56 randomized controlled trials with 4060 participants analyzed the effect of eight psychosocial interventions on seven immune outcomes [481]. Psychosocial interventions, particularly cognitive behavioral therapy, significantly reduced proinflammatory markers and increased beneficial immune functions, with changes lasting at least six months after completion of therapy.

Integration into other systems

C1q is involved in a broad array of physiologic functions beyond its role in complement activity. Besides synapse pruning, these include dendritic cell development, apoptotic cell clearance, placental development, and cell metabolism [85,140,141].

Metabolism and immunity have been interwoven since the emergence of life. The role of proinflammatory cytokines, particularly of macrophage origin, in insulin resistance, obesity, and diabetes was established in the 1990s; and later work indicates that the metabolic state is a critical determinant of immune function. Current experimentation in the field of immunometabolism targets possible interventions to disrupt interactions at the basis of chronic disease, particularly obesity [482].

Coagulation factor XIII cross-links fibrin and bacteria and then exerts direct antimicrobial activity [483,484]. In another example of coevolution, clotting factor X coats circulating common cold adenoviruses and targets them to TLR4 on macrophages, with resultant production of proinflammatory cytokines that can contribute to eventual removal of the virus [485,486]. Moreover, secretory products from phagocytic leukocytes (granule enzymes, cytokines) and damage-associated molecular patterns (DAMPs) can influence all aspects of thrombosis [487,488]. (See "Toll-like receptors: Roles in disease and therapy".)

Erythrocytes modulate innate immunity by binding and scavenging circulating chemokines, nucleic acids, and pathogens [489].

Proteins of the innate immune system with both antimicrobial and anti-inflammatory potential attach to high density lipoprotein (HDL) cholesterol [490,491].

Alpha-intercalated cells in the collecting duct of the kidney are essential for maintaining acid-base balance. They also defend against upper and lower urinary tract infection by binding uropathogenic E. coli and then acidifying the urine and secreting the bacteriostatic protein lipocalin 2 [118].

Hepatocytes express PRRs, including TLRs 2, 3, and 4, and when challenged by pathogens, can deliver innate immune responses in the liver or the acute-phase response systemically. Hepatocytes play a direct role in the innate defense against hepatitis C and hepatitis B viruses [186].

Studies in mice show that each cardiac muscle cell touches an average of five cardiac macrophages. To function normally, muscle cells eject spent mitochondria and muscle proteins in small packets called exophers. If exophers are not cleared by macrophages, dysfunctional mitochondria accumulate in the muscle cells, and ventricular function is impaired [257,258].

The pervasive distribution of host defense immune capacity and its attendant inflammation, essential to survival through the reproductive period, can as life goes on also contribute to the pathogenesis of organ-specific diseases (eg, Alzheimer and other neurodegenerative diseases [267,269,271,279,282,472]), autoimmune disease (such as chronic active hepatitis), cancer, or atherosclerosis. Better understanding of these various interactions could allow wiser therapeutic interventions.


The innate immune system refers to inherited, germ-line defense mechanisms that are directed against molecular components found only in micro-organisms. They have been refined by evolution over generations and can be "trained" through epigenetic changes to express enhanced response to the original pathogen and also to other microbial threats. (See 'Innate, adaptive, and trained innate immunity' above.)

In addition to providing a first line of defense against microbes, the innate immune system activates and instructs adaptive immune responses, regulates inflammation, and mediates immune homeostasis (the balance between opposing proinflammatory and anti-inflammatory processes). (See 'Critical functions' above.)

The cells of the innate immune system use pattern recognition receptors (PRRs), which recognize pathogen-associated molecular patterns (PAMPs) on micro-organisms, and communicate through cytokines. PRRs also recognize and direct removal of components of damaged tissue (damage-associated molecular patterns, DAMPs) (table 1 and table 2). (See 'Microbial detection through pattern recognition' above and 'Cells of the innate immune system' above.)

Activation of the innate immune system begins with resident cells in the tissues at the site of the insult (macrophages, epithelial cells, mast cells, innate lymphoid cells [ILCs]). If the threat of infection accelerates, these cells recruit other cells (neutrophils, natural killer [NK] cells, dendritic cells, monocytes, platelets) from the circulation into the inflamed tissues. (See 'Cells of the innate immune system' above.)

Many of the same cells and mechanisms used to recognize and attack microbes and initiate inflammatory reactions are also used to clear away damaged and dying cells and their cell components, then downregulate inflammation to maintain homeostasis within the host. (See 'Homeostasis in the innate immune system' above.)

The innate immune system extends its capacity to react quickly to invading micro-organisms by communicating directly, cell-to-cell, with adaptive immune cells and releasing mediators that activate and instruct the adaptive immune system. In these ways, innate immune mechanisms enhance and instruct antigen-specific T and B lymphocyte responses and the development of immunologic memory. (See 'Innate immunity instructs adaptive immunity' above.)

The cells and circulating factors of the innate immune system represent a potent first line of defense, but they cannot function optimally without the specific antibodies and sensitized T cells that effect adaptive immunity. Thus, the adaptive immune system enhances innate immunity. (See 'Innate immunity instructs adaptive immunity' above.)

As basic physiologic systems evolved, some incorporated functions of the innate immune system to contribute to their defense or to amplify their primary role in physiology. (See 'Integration of innate immunity into other physiologic systems' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.

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