Innate immunity in allergy

Abstract

Innate immune system quickly responds to invasion of microbes and foreign substances through the extracellular and intracellular sensing receptors, which recognize distinctive molecular and structural patterns. The recognition of innate immune receptors leads to the induction of inflammatory and adaptive immune responses by activating downstream signaling pathways. Allergy is an immune-related disease and results from a hypersensitive immune response to harmless substances in the environment. However, less is known about the activation of innate immunity during exposure to allergens. New insights into the innate immune system by sensors and their signaling cascades provide us with more important clues and a framework for understanding allergy disorders. In this review, we will focus on recent advances in the innate immune sensing system.

Keywords: inflammasome; pattern recognition receptors; pyroptosis.

Figure 1

TLR‐mediated signaling pathway. All TLR proteins have LRR and TIR domains (in the balloon). Individual TLRs recognize different ligands, such as LPS, triacyl lipopeptide, diacyl lipopeptides, bacterial flagellin, DNA, and RNA. TLRs localize at the cell surface or in endosomes. TLRs recruit two adaptor proteins, MyD88 and TRIF. The ligand engagement of TLRs induces the formation of the Myddosome (MyD88 and IRAKs) and activates the NF‐κB pathway. TLR3 and TLR4 also induce the formation of a signalosome (TRIF, TRAF3, TBK1, and IKKi [IKKε]). Activated IRF‐3 induces type I IFN production. Th1/Th2 polarization into either a Th1 immune response or Th2 immune response is dependent on the signal dose through TLRs. IKKi, inducible inhibitor of NF‐κB (IκB) kinase; IRAK, IL‐1 receptor‐associated kinase; IRF‐3, IFN regulatory factor 3; LPS, lipopolysaccharide; LRR, leucine‐rich repeat; MyD88, myeloid differentiation primary response 88; NF‐κB, nuclear factor‐kappa B; TBK1, TRAF‐associated NF‐κB activator (TANK)‐binding kinase 1; Th1, T‐helper 1; Th2, T‐helper 2; TIR, Toll/interleukin‐1 receptor; TLR, Toll‐like receptor; TM, transmembrane; TRAF3, TNF receptor‐associated factor 3; TRIF, TIR‐domain‐containing adaptor inducing interferon (IFN)‐β

Figure 2

Type II transmembrane CLR. Type II transmembrane CLR proteins possess a single CRD. Dectin‐1 (CLEC7A) recognizes fungal wall‐derived β‐glucans. Dectin‐2 (CLEC6A) recognizes the structure of α‐mannans. Mincle (CLEC4E) recognizes diverse glycolipids including TDM, Glc‐DAG, and MGDG. Dectin‐1 transduces the signal through its ITAM‐like motif. Both Dectin‐2 and Mincle associate with FcRγ for signaling. Ligand‐bound CLRs result in the Syk‐dependent formation of the CBM (CARD9‐BCL10‐MALT1) complex. The CBM complex activates the pathways of MAPK and NF‐κB, leading to pro‐inflammatory cytokine production. BCL10, B‐cell CLL/lymphoma 10; CARD9, caspase‐recruitment domain 9; CLR, C‐type lectin receptor; CRD, carbohydrate recognition domain; Dectin‐1, dendritic cell (DC)‐associated C‐type lectin‐1; Dectin‐2, DC‐associated C‐type lectin‐2; FcRγ, Fc receptor common gamma chain; Glc‐DAG, glucosyl diacylglycerol; ITAM, immunoreceptor tyrosine‐based activation motif; MALT1, mucosa‐associated lymphoid tissue protein 1; MAPK, mitogen‐activated protein kinase; MGDG, monoglucosyldiacylglycerol; Mincle, macrophage‐inducible C‐type lectin; NF‐κB, nuclear factor‐kappa B; Syk, spleen tyrosine kinase; TDM, trehalose‐6,6′‐dimycolate

Figure 3

Nucleic acid sensors. RIG‐I and MDA5 have two CARD domains at the N‐terminus and a helicase domain at the center. Both RIG‐I and MDA5 bind viral RNAs bearing 5’‐triphosphate or 5’‐diphosphate distinct from the mammalian RNA with 5’ cap structure. After viral RNA recognition, RIG‐I and MDA5 interact with IPS‐1 (MAVS) through CARD‐CARD interactions. IPS‐1 (MAVS) is localized on the mitochondrial outer membrane. Aggregated IPS‐1 (MAVS) activates TBK1 and IKKi (IKKε) through TRAFs, leading to induction of type I IFN via phosphorylation of IRF‐3/7. cGAS binds dsDNA and produces a second messenger, cGAMP, from ATP and GTP. cGAMP binds to STING localized on the ER membrane and induces type I IFN production via the TBK1/IRF‐3 pathway. CARD, caspase‐recruitment domain; cGAMP, cyclic GMP‐AMP; cGAS, cyclic GMP‐AMP synthase; ER, endoplasmic reticulum; IKKi, inducible inhibitor of NF‐κB (IκB) kinase; IPS‐1, IFN‐β promoter stimulator 1; IRF, IFN regulatory factor; MDA5, melanoma differentiation‐associated gene 5; RIG‐I, retinoic acid‐inducible gene I; STING, stimulator of IFN genes; TBK1, TRAF‐associated NF‐κB activator (TANK)‐binding kinase 1; TRAF, TNF receptor‐associated factor

Figure 4

NLR family, PYD‐containing non‐NLR proteins, and NOD signaling. In the NLR family, there are five major subfamilies based on the unique N‐terminal domain structure: NLRA (AD‐type), NLRB (BIR‐type), NLRC (CARD‐type), NLRP (PYD‐type) and NLRX (X‐type). All family proteins have a NACHT domain in the central region. NOD2 senses bacterial cell wall‐derived peptidoglycan derivative MDP; however, NOD1 only senses Gram‐negative bacteria‐derived iE‐DAP. After sensing ligands, NODs oligomerize and interact with RIPK2 through the CARD domain. RIPK2 further activates downstream cascades and MAPK and NF‐κB pathways, leading to cytokine production. AD, transactivation domain; BIR, baculoviral inhibitor of apoptosis repeat; CARD, caspase‐recruitment domain; FIIND, function‐to‐find domain; HIN200, hematopoietic interferon‐inducible nuclear antigens with 200 amino acid repeats; iE‐DAP, γ‐D‐glutamyl‐meso‐diaminopimelic acid; LRR, leucine‐rich repeat; MAPK, mitogen‐activated protein kinase; MDP, muramyl dipeptide; NACHT, NAIP, CIIA, HeT‐E, and TEP1; NF‐κB, nuclear factor‐kappa B; NOD1, nucleotide‐binding oligomerization domain‐containing protein 1; NOD2, nucleotide‐binding oligomerization domain‐containing protein 2; PYD, Pyrin domain; RIPK2, receptor‐interacting serine/threonine‐protein kinase 2

Figure 5

Inflammasome. NLRP3 forms a complex with ASC through their PYD binding each other and recruiting the CARD domain of pro‐caspase‐1. After assembly, this multimeric complex is called the inflammasome (upper box). In the canonical inflammasome assembly, ligand‐sensing NLRs (NLRP1, NLRP3, NLRP6, NAIP/NLRC4, and AIM2) (blue balloons) form multisubunit disk‐like structures comprising an inner ring and outer ring. Pro‐caspase‐1 is located in the central portion (black balloon). Activated caspase‐1 processes IL‐1β/IL‐18 and triggers proteolytic cleavage of GSDMD (brown boxes). In the noncanonical inflammasomes, caspase‐11 and caspase‐8 participate in the cytoplasmic LPS sensing pathway and Dectin‐1‐CBM signaling pathway, respectively (pink boxes). Activated caspase‐11 cleaves GSDMD similarly to caspase‐1 (red arrow). GSDMD‐derived NTD induces pore formation for pyroptosis and stimulates the NLRP3 inflammasome pathway (black arrows). Activated caspase‐8 with FADD is capable of cleaving pro‐IL‐1β/pro‐IL‐18 (red arrow). Caspase‐8 may positively regulate NLRP3 inflammasome pathway (red arrow). AIM2, absent in melanoma 2; ASC, apoptosis‐associated speck‐like protein containing a CARD; CARD, caspase‐recruitment domain; CBM, CARD9‐BCL10‐MALT1; Dectin‐1, lipopolysaccharide; GSDMD, gasdermin D; LPS, lipopolysaccharide; LTA, lipoteichoic acid; NAIP, NLR family apoptosis inhibitory protein; NLRC4, NLR family CARD domain containing 4; NLRP1, NLR family Pyrin domain containing 3; NLRP3, NLR family Pyrin domain containing 3; NLRP6, NLR family Pyrin domain containing 6; NTD, N‐terminal domain; PYD, Pyrin domain

Figure 6

ALPK1‐TIFA‐NF‐κB axis. Once HBP and ADP‐Hep, bacterial products of the LPS biosynthetic pathway, are transported into the host cell, both types of sugars activate NF‐κB signaling pathway. ADP‐heptose 7‐P, which is converted from HBP by host enzyme NMNAT, interacts to N‐terminus of ALPK1. Activated ALPK1 phosphorylates TIFA and induces the TIFA oligomerization with TRAFs, named TIFAsome. ADP‐Hep can also interact with ALPK1 in the same fashion, leading to the activation of NF‐κB and inflammation. ADP‐Hep has much more potent NF‐κB activator than HBP. ADP‐Hep, ADP‐β‐D‐manno‐heptose; ALPK1, alpha‐kinase 1; HBP, D‐glycero‐β‐D‐manno‐heptose 1,7‐bisphosphate; LPS, lipopolysaccharide; NMNAT, nicotinamide mononucleotide adenylyltransferase; TIFA, TRAF‐interacting protein with forkhead‐associated domain; TRAF, TNF receptor‐associated factor