Signaling pathways triggered by TLR3, TLR4 and TLR1–TLR2. (A) The TLR4–MD-2 complex engages with LPS on the cell surface via LBP and CD14 (data not shown) and then recruits a TIR domain-containing adapter complex including TIRAP and MyD88. The TLR4–MD-2–LPS complex is subsequently trafficked to the endosome, where it recruits TRAM and TRIF adapters. (B) TIRAP–MyD88 recruits IRAK family members and TRAF6 to activate TAK1. (C) The TAK1 complex activates the IKK complex composed of IKKα, IKKβ and NEMO (IKKγ), which catalyze phosphorylation of IκB proteins. Phosphorylated IκB proteins are degraded, allowing NF-κB to translocate to the nucleus. (D) TAK1 simultaneously activates the MAPK pathway. The activation of NF-κB and MAPK results in induction of inflammatory cytokine genes (MyD88-dependent pathway). TRAM–TRIF recruits (E) TRAF6 and RIP-1 for activation of TAK1 as well as (F) TRAF3 for activation of TBK1–IKKi that phosphorylates and activates IRF3. Whereas NF-κB and MAPK regulate expression of inflammatory cytokine genes in both pathways, IRF3 regulates expression of type I IFN in the TRIF-dependent pathway only. (G) TLR3 resides in the endosome and recognizes dsRNA. It recruits TRIF to activate the TRIF-dependent pathway. (H) TLR1–TLR2 recognizes bacterial triacylated lipopeptide and recruits TIRAP and MyD88 at the plasma membrane to activate the MyD88-dependent pathway.

Recognition of viral nucleic acids by TLRs, RLRs and the cytosolic DNA sensor. (A) In pDCs, TLR7 and TLR9 reside in the ER and interact with UNC93B and are trafficked to the endosome to recognize viral ssRNA and DNA, respectively. These TLRs recruit MyD88, IRAK4 and TRAF6, which in turn activates TAK1, IRF5 and TRAF3. TAK1 mediates activation of NF-κB and MAPK, which leads to the induction of inflammatory cytokine genes. IRF5 also mediates inflammatory cytokine expression. TRAF3 activates IRAK1 and IKKα, which catalyze the phosphorylation of IRF7 and induce type I IFN genes. OPN is involved in the activation of IRF7. IRF8 facilitates NF-κB and IRF7 activation. (B) In addition, pDCs exhibit constitutive autophagy induction, which deliver viral RNA to the endosome or lysosome, where TLR7 is expressed. (C) In cDCs, macrophages and fibroblast cells, viral RNA species are preferentially recognized by RLRs. RIG-I and MDA5 recruit the adapter IPS-1 via CARDs. IPS-1 is localized to mitochondria, and recruits TRADD, which then forms a complex with FADD, caspase-8 and caspase-10 to activate NF-κB. TRADD also recruits TRAF3 to activate the TBK1–IKKi–IRF3 axis. FADD is also implicated in IRF3 activation. STING (also known as MITA) localizes to (D) mitochondria or (E) ER; in mitochondria, STING (MITA) interacts with IPS-1 and RIG-I and activates NF-κB and IRF3. (F) Cytoplasmic dsDNA is thought to be sensed by an as-yet-undefined host DNA sensor. In the ER, STING (MITA) plays an essential role in the responses to dsDNA. DsDNA activates NF-κB and IRF3 via the IKK complex (data not shown) and TBK1–IKKi, respectively.

Sensing PAMPs by NOD1, NOD2, dectin-1 and TLRs. (A) NOD1 and NOD2 sense intracellular iE-DAP and MDP, respectively, and recruit CARD proteins RICK and CARD9. RICK activates MAPK and NF-κB via TAK1; CARD9 activates MAPK. (B) Dectin-1 senses fungal infection and recruits the Syk, which leads to activation of NF-κB through the CARD9–Bcl-10–MALT1 complex. (C) CARD9 is also involved in TLR-mediated MAPK activation. Activation of NF-κB and MAPK results in induction of inflammatory cytokine genes.

Activation of IL-1β by inflammasomes and other pathways. The three types of inflammasome shown here can recruit caspase-1, which converts pro-IL-1β into the mature form, IL-1β. (A) MDP, R837, R848, bacterial RNA, DNA viruses and several intracellular bacteria activate the NALP3 inflammasome. NALP3 forms a complex with the adapters ASC and CARDINAL to recruit caspase-1. (B) Extracellular ATP activates the P2X7 purine receptor, which then helps to allow the pannexin-1 receptor to cause K⁺ efflux, which enhances activation of the NALP3 (and NALP1) inflammasome. (C) Some microbial toxins, and (D) gout-associated uric acid crystals, calcium pyrophosphate dihydrate crystals (CPPD), UV-B irradiation, alum, silica, asbestos and amyloid-β also induce activation of the NALP3 inflammasome. These stimuli induce ROS production or release of cathepsins during lysosome rupture. (E) Flagellin activates IPAF and NAIP5. The IPAF inflammasome recruits ASC and caspase-1. (F) The NALP1 inflammasome senses Bacillus anthrax LT and activates caspase-1 via ASC. (G) TLR ligands also induce the synthesis of pro-IL-1β.