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INTRODUCTION

SUMMARY

The innate immune system provides immediate protection against infection using effector mechanisms that include phagocytosis of infected cells and production of proinflammatory cytokines. These responses depend on the detection of microbes by innate immune cells, mediated by a sensory apparatus consisting of cell surface proteins of the Toll-like receptor, NOD (nucleotide-binding oligomerization domain)-like receptor, RIG-I–like receptor, and C-type lectin receptor families and by cGAS and caspases 4/5/11. The biochemical events that follow receptor activation converge on nuclear factor-κB, activator protein 1, cAMP response element-binding protein (CREB), and the interferon response factors (IRFs) transcription factors that induce genes necessary for the inflammatory response. Among these are genes encoding cytokines and chemokines that recruit additional innate immune cells to the infection site. Dendritic cells are innate immune cells specialized for antigen presentation to the adaptive immune system; their recruitment to the site of infection is important for activation of an antigen-specific adaptive immune response. Innate immunity serves an essential role in the initial containment of microorganisms by promoting their engulfment and killing and stimulates an adaptive immune response to develop in the days and weeks that follow. Susceptibility to infection in humans is strongly heritable, and among the many loci that influence it, encoding proteins vital to the innate immune response are of central importance. Moreover, autoinflammatory and autoimmune diseases are dependent on the activation of innate immune signaling pathways.

Acronyms and Abbreviations

AMP, adenosine monophosphate; AP, adapter protein; ASC, apoptosis-associated speck-like protein containing a CARD; BCL10, B-cell lymphoma/leukemia 10; BIR, baculovirus inhibitor of apoptosis repeat; CARD, caspase activating and recruitment domain; CD, cluster of differentiation; cGAMP, cyclic GMP:AMP; cGAS, cyclic AMP/GMP synthetase; CLR, C-type lectin receptor; CREB, cyclic AMP response element-binding protein; CTLA, cytotoxic T-lymphocyte antigen; DAP, γ-d-glutamyldiaminopimelic acid; DC-SIGN, DC-specific ICAM3-grabbing non-integrin; DEAF-1, deformed epidermal autoregulatory factor-1; dectin, DC-associated C-type lectin; dsRNA, double-stranded RNA; ECSIT, evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial; ERK, extracellular signal-regulated kinase; FADD, Fas-associated death domain; FcRγ, Fc receptor γ-chain; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-monocyte colony-stimulating factor; GMP, guanosine monophosphate; IFN, interferon; IκB; inhibitor of κB; IKK, IκB kinase; IL, interleukin; IPS-1, IFN-β promoter stimulator 1; IRAK, interleukin-1 receptor-associated kinase; IRF, interferon response factor; ITAM, immunoreceptor tyrosine (Y)-based activation motif; JAK, Janus kinase; JNK, c-Jun N-terminal kinase; LAMP5, lysosome-associated membrane glycoprotein 5; LBP, lipopolysaccharide binding protein; LPS, lipopolysaccharide; LRR, leucine-rich repeat; LUBAC, linear ubiquitin chain assembly complex; MAL, MyD88 adaptor-like protein; MALT-1, mucosa-associated lymphoid tissue lymphoma translocation gene 1; MAP3K7/8, mitogen-activated protein kinase kinase kinase 7/8; MAVS, mitochondrial antiviral signaling protein; MDA5, melanoma differentiation-associated gene 5; MDP, muramyl dipeptide; MEK, dual specificity mitogen-activated protein kinase kinase; MHC, major histocompatibility complex; Mincle, macrophage-inducible C-type lectin; Mst, mammalian STE20-like kinase; MTD, mitochondrial targeting domain; MyD88, myeloid differentiation primary response 88 protein; NACHT, a nucleotide-binding domain present in NAIP, CIITA, HET-E, and TP-1; NADPH, nicotinamide adenine dinucleotide phosphate; NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; NK, natural killer; NLR, NOD-like receptor; NOD, nucleotide-binding oligomerization ...

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