The intersection of cell death and inflammasome activation

Abstract

Inflammasomes sense cellular danger to activate the cysteine-aspartic protease caspase-1, which processes precursor interleukin-1β (IL-1β) and IL-18 into their mature bioactive fragments. In addition, activated caspase-1 or the related inflammatory caspase, caspase-11, can cleave gasdermin D to induce a lytic cell death, termed pyroptosis. The intertwining of IL-1β activation and cell death is further highlighted by research showing that the extrinsic apoptotic caspase, caspase-8, may, like caspase-1, directly process IL-1β, activate the NLRP3 inflammasome itself, or bind to inflammasome complexes to induce apoptotic cell death. Similarly, RIPK3- and MLKL-dependent necroptotic signaling can activate the NLRP3 inflammasome to drive IL-1β inflammatory responses in vivo. Here, we review the mechanisms by which cell death signaling activates inflammasomes to initiate IL-1β-driven inflammation, and highlight the clinical relevance of these findings to heritable autoinflammatory diseases. We also discuss whether the act of cell death can be separated from IL-1β secretion and evaluate studies suggesting that several cell death regulatory proteins can directly interact with, and modulate the function of, inflammasome and IL-1β containing protein complexes.

Keywords: Apoptosis; Caspase-1; Caspase-8; Inflammasome; MLKL; Necroptosis; Pyroptosis; RIPK3.

Fig. 1

Caspase-1 mediated pyroptosis. Top panel. Several reports indicate that pyroptosis is executed by Gasdermin D (GSDMD) which is processed and activated by inflammasome-associated caspase-1 (i.e. NLPR3, AIM2, NLRC4) or LPS-activated caspase-11. Caspase-11 activated GSDMD can also result in potassium efflux to indirectly activate NLRP3 and IL-1β processing and secretion. Inflammasome sensors (such as NLRP3 and AIM2) utilize the adaptor protein ASC that, other than recruiting and activating caspase-1, can also bind and activate caspase-8 to induce apoptotic cell death. Bottom panel. A recent study presented evidence suggesting that caspase-11-induced pyroptosis results from caspase-11 cleavage of Pannexin-1, triggering ATP release and P2X7-dependent cytolysis. Pannexin-1 cleavage also promotes potassium efflux to activate NLRP3 indirectly. See main text for references

Fig. 2

Apoptotic and necroptotic signaling and their activation of IL-1β. 1. Caspase-8 directly processes precursor IL-1β in response to death receptor, TLR or Dectin-1 signaling. 2. Following IAP loss, and possibly A20, TLR- or TNF-induced RIPK3 promotes caspase-8 signaling that induces NLRP3 activation. Although experimental evidence has yet to be reported, this may occur via triggering potassium efflux at the onset of the cells demise. 3. In the absence of caspase-8, TLR and TNF signaling triggers RIPK3 kinase activity and phosphorylation of its substrate MLKL. MLKL activates NLRP3 to induce IL-1β inflammatory responses. See main text for references

Fig. 3

Association of TLR and TNF receptor signaling components with inflammasome protein complexes. cFLIP reportedly interacts with NLRP3 (and AIM2) to promote inflammasome assembly, while HOIL-1, part of the LUBAC complex, decorates ASC with linear ubiquitin chains to induce ASC speck formation. Similarly, following RNA viral infection, MAVS-induced TRAF3 E3 ligase activity has been suggested to modify ASC with K63-linked ubiquitin chains to promote its aggregation. A20 removes K63-linked ubiquitin chains from K133 of IL-1β to limit its processing and activation in response to TLR signaling. See main text for references