Novel perspectives on non-canonical inflammasome activation

Abstract

Inflammasomes are cytosolic multi-protein complexes that regulate the secretion of the proinflammatory cytokines, IL-1β and IL-18, and induce pyroptosis, an inflammatory form of cell death. The NLRP3 inflammasome is the most well-characterized member of this family and functions by sensing intracellular pathogen- and damage-associated molecular patterns and activating caspase-1, which processes the biologically inactive IL-1β and IL-18 precursors into active cytokines. Recent studies have identified an alternative mechanism of inflammasome activation, termed the non-canonical inflammasome, which is triggered by cytosolic sensing of lipopolysaccharide (LPS) derived from bacteria that have escaped phagolysosomes. This pathway is independent of Toll-like receptor 4 (TLR4), the well-known extracellular receptor for LPS, but instead depends on the inflammatory protease, caspase-11. Although our understanding of caspase-11 activation is still in its infancy, it appears to be an essential mediator of septic shock and attenuates intestinal inflammation. In this review, we bring together the latest data on the roles of caspase-11 and the mechanisms underlying caspase-11-mediated activation of the non-canonical inflammasome, and consider the implications of this pathway on TLR4-independent immune responses to LPS.

Keywords: IL-18; IL-1β; LPS; NLRP3; caspase-1; caspase-11.

Figure 1

Schematic view of the TLR4 signaling pathway. Notes: Upon binding of lipopolysaccharide (LPS) to the TLR4 complex (TLR4–LBP–CD14–MD2), TLR4 signals through MyD88-dependent and/or MyD88-independent pathways. The MyD88-dependent pathway is triggered by MyD88 recruitment of TRAF6 and IRAKs, which, in turn, results in activation of TAK1. TAK1 phosphorylates IKKβ, leading to IκBa and activation of NF-κB. NF-κB translocates to the nucleus to promote the transcription of proinflammatory genes (such as IL-1α/β, IL-18, IL-6, and TNFα). The MyD88-independent pathway relies on TRIF recruitment of RIP1 or TRAF3. TRAF3 activates IRF3 through TBK1, inducing transcription of type I interferons (IFNs) and IFN-inducible genes. Abbreviations: TLR4, Toll-like receptor 4; MD2, Myeloid differentiation factor 2; TIRAP, TIR domain-containing adaptor protein; TRAM, TRIF-related adaptor molecule; MyD88, myeloid differentiation primary response gene 88; TRIF, TIR-domain-containing adapter-inducing interferon-β; TNFα, tumor necrosis factor α; TRAF6, TNF-receptor associated factor 6; IRAKs, IL-1 receptor-associated kinases; TGFβ, Transforming growth factor beta; TAK1, TGFβ-activated kinase; IRF3, interferon regulatory factor 3; IL, interleukin; LBP, lipopolysaccharide binding protein; RIP1, receptor-interacting protein 1; IKKε, I-kappa-B kinase epsilon; IFN, interferon.

Figure 2

Canonical and noncanonical pathways of inflammasome activation. Notes: (A) Canonical inflammasome activation (canonical pathway). (i) Lipopolysaccharide (LPS) is detected by TLR4, (ii) initiating the NF-κB signaling pathway. (iii) This upregulates transcription of the inactive precursor pro-IL-1β, pro-IL-18, and pro-caspase-11. (iv) A second inflammatory signal (eg, a pathogen- [PAMP] or danger-associated molecular pattern [DAMP] is detected, (v) triggering the formation of the molecular complex – the inflammasome. (vi) This initiates cleavage and activation of pro-caspase-1, pro-IL-1β, and pro-IL-18, (vii) allowing secretion of IL-1β and IL-18 from the cell. (B) Non-canonical inflammasome activation (non-canonical pathway). (i) When LPS is present in abundance or is contained within vacuoles, it is able to enter the intracellular environment independent of TLR4. (ii) GBPs promote vacuolar lysis, causing entry of LPS into the cytosol of the cell. (iii) Pro-caspase-11 detects cytosolic LPS, (iv) initiating the formation of the inflammasome, as well as (v) pyroptosis of the cell. (vi) Formation of the NLRP3 inflammasome also leads to the release of cytokines by similar mechanisms to the canonical pathway. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase-recruitment domain; NLRP3, The NOD-like receptor pyrin-domain containing 3; TLR4, Toll-like receptor 4; IL, interleukin; GBPs, guanylate-binding proteins.