Cell Death-Associated Molecular-Pattern Molecules: Inflammatory Signaling and Control

Figure 1

An integrative overview of intracellular signaling pathways by the IL-1R, TLRs, NLRs, and CLRs upon an innate immune response to microbial infection or cell death. Upon binding of PAMPs, DAMPs, or cytokines (IL-1α or IL-1β) the recruitment and assembly of high oligomeric platforms containing one more subunits of receptors, adaptors, inhibitors, ubiquitin ligase, and an initiator caspases (caspase-1, -8, or -5) occur. Following phosphorylation, ubiquitination, and degradation, certain components of each platform and an inflammatory signaling pathway are triggered. TLR and IL-1R receptor platforms recruit and activate MyD88 protein via intracellular Toll/IL-1R homology (TIR) domain. TIR domain interacts with MyD88, TIRAP/Mal, or TRIF/TRAM, which are proteins sharing a similar TIR domain. These proteins interact with the death domain of serine/threonine kinase (IRAK) family and IRAKs, which in turn promote the phosphorylation and activation the interferon regulatory factors (IRF1, 3, 5, 7), leading to the production of type I interferons (IFN-α and -β) in a cell-type-specific manner. IRAKs also cause the phosphorylation and activation of TAK1/TAB2/3 which in turn promote the phosphorylation of the inhibitor of NF-κB (IKK subunits α, β and γ) and thereby NF-κB activation. The different (NOD)-like receptors (NLRs), for example, NLRP3, interact with specific PAMPs or DAMPs to gather an inflammasome platform, via the ASC adaptor, which recruits and activates caspase-1, which in turn cleaves and releases IL-1β and IL-18. Some myeloid C-type lectin receptors (CLRs), for example, Dectin-1 recruits Syk through a phosphotyrosine in the hemITAM motif. Syk induces the activation of the NALP3 inflammasome, leading to the processing of pro-IL-1β. See text for further details.