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. 2019 Jun 13;20(12):2876. doi: 10.3390/ijms20122876

Figure 2.

Figure 2

Diagram showing the different molecular mechanisms of non-canonical NLRP3 inflammasome activations. Left panel: Non-canonical caspase-8-dependent NLRP3 activation. TLR4 stimulation by PAMPs and/or DAMPs activates RIP1–FADD-caspase-8 intracellular signaling, which, besides promoting the NF-kB transcription step, can activate directly canonical NLRP3 oligomerization and assembly. In addition, fungi PAMPS (i.e., Candida albicans, fungal cell wall component β-glucans, and mycobacteria), via dectin-1 stimulation, can promote IL-1β transcription as well as the formation and activation of a mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1)–caspase-8– adaptor protein (ASC) complex, which contributes to processing and release of IL-1β. Right panel: Non-canonical caspase-11-dependent NLRP3 activation. In the first step, Gram-negative bacteria activate the TLR4–MyD88 and tumor necrosis factor receptor (TRIF) pathways, with consequent nuclear translocation of NF-κB, which promotes the transcription of IL-1β, IL-18, and NLRP3 as well as interferon regulatory factor (IRF)-3 and IRF7 genes. The IRF3–IRF7 complex (1) elicits the expression of IFN-α/β (2) that binds the interferon (IFN)-α/β receptor 1 IFNAR1/IFNAR2 receptor (3), leading to activation of the janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway (4) and transcription of caspase-11 gene (5). In the second step, unidentified scaffold proteins or receptors induced by Gram-negative bacteria cleave and activate caspase-11, which induces pyroptosis as well as high-mobility group box 1 (HMGB1) and IL-1α release, and promotes the activation of NLRP3–ASC–caspase-1 pathway. Caspase-1 activation promotes also pyroptosis and HMGB1 release.