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. Author manuscript; available in PMC: 2017 Dec 15.
Published in final edited form as: Cell. 2016 Dec 15;167(7):1693–1704. doi: 10.1016/j.cell.2016.11.047

Figure 1. Pyroptosis induction by noncanonical and canonical inflammasomes.

Figure 1

Toll-like receptors (TLRs) and/or interferons (IFNs)-mediated priming upregulate the expression of guanylate binding proteins (GBPs) critical for bacterial vacuole lysis and/or pattern-associated molecular patterns (PAMPs, including LPS and bacterial DNA) exposure, sensors (NLRP3, caspase-11) and cytokine precursor (pro-IL-1β). Of note, MyD88 and TRIF-dependent signaling downstream of TLRs can alternatively prime NLRP3 in a transcription-independent manner. Upon detection of their respective agonists, NLRP3, NLRC4, NLRP1b, AIM2 and pyrin assemble canonical inflammasomes containing adaptor ASC and leading to the activation of caspase-1 that controls the maturation of pro-cytokines (pro-IL-1β and pro-IL-18) and pyroptosis through the cleavage of GSDMD among other mechanisms. LPS of some Gram-negative bacteria enter the cytosol through outer membrane vesicles (OMVs) or at the surface of cytosolic bacteria. Cytosolic LPS binds caspase-11 and triggers the oligomerization of the noncanonical inflammasome; Caspase-11 controls pyroptosis through the cleavage of GSDMD and pannexin-1. Pannexin-1-mediated release of ATP triggers the opening of P2X7-dependent pores, while GSDMD N-terminal fragments directly assemble to form pores. Membrane disruption leads to pyroptosis lytic cell death releasing alarmins and proinflammatory cytokines. It should be noted that IL-1β secretion can occur independently of cell lysis. Non-canonical inflammasome also controls caspase-1 activation mediated by the NLRP3 canonical inflammasome through pannexin-1 and GSDMD cleavages in a cell intrinsic manner involving K+ efflux. (Green: priming; blue: activation; purple: effector mechanisms.)