The Inflammasome Drives GSDMD-Independent Secondary Pyroptosis and IL-1 Release in the Absence of Caspase-1 Protease Activity

Abstract

SummaryInflammasomes activate the protease caspase-1, which cleaves interleukin-1β and interleukin-18 to generate the mature cytokines and controls their secretion and a form of inflammatory cell death called pyroptosis. By generating mice expressing enzymatically inactive caspase-1C284A, we provide genetic evidence that caspase-1 protease activity is required for canonical IL-1 secretion, pyroptosis, and inflammasome-mediated immunity. In caspase-1-deficient cells, caspase-8 can be activated at the inflammasome. Using mice either lacking the pyroptosis effector gasdermin D (GSDMD) or expressing caspase-1C284A, we found that GSDMD-dependent pyroptosis prevented caspase-8 activation at the inflammasome. In the absence of GSDMD-dependent pyroptosis, the inflammasome engaged a delayed, alternative form of lytic cell death that was accompanied by the release of large amounts of mature IL-1 and contributed to host protection. Features of this cell death modality distinguished it from apoptosis, suggesting it may represent a distinct form of pro-inflammatory regulated necrosis.

Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients

“…Invalidation of GSDMD did not impact cell death kinetics as much as CASP1 invalidation. Such differences in cell death kinetics have been reported in several studies comparing cell death kinetics upon invalidation of individual inflammasome components and likely reflect the existence of alternative/secondary cell death pathways (Pierini et al, 2012;Sagulenko et al, 2013;Schneider et al, 2017).…”

Guanylate-binding proteins at the crossroad of noncanonical inflammasome activation during bacterial infections

“…Canonical inflammasomes activators induce caspase‐1 promoting not only cleavage of IL‐1β but also its early secretion by GSDMD pores . In that scenario, caspase‐8 activation is inhibited . However, GSDMD‐deficient cells exhibit a delayed form of lytic death in which caspase‐8 is activated and might drive the secretion of similar levels of IL‐1β compared to wild‐type cells.…”

“…Interestingly, cells deficient in caspase‐1 secrete reduced levels of mature IL‐1β even at late time points. The GSDMD‐independent mechanisms of IL‐1β release may promote host protection against pathogens, at least to some extent, since GSDMD‐deficient mice show a less severe F. novicida infection than caspase‐1‐deficient mice . Intriguingly, the mechanism of IL‐1β maturation itself empowers its relocation from the cytosol to the phosphatidylinositol 4,5‐bisphosphate microdomains in the plasma membrane.…”

“…95 In that scenario, caspase-8 activation is inhibited. 96 However, GSDMD-deficient cells exhibit a delayed form of lytic death in which caspase-8 is activated and might drive the secretion of similar levels of IL-1 compared to wild-type cells. Interestingly, cells deficient in caspase-1 secrete reduced levels of mature IL-1 even at late time points.…”

“…The GSDMD-independent mechanisms of IL-1 release may promote host protection against pathogens, at least to some extent, since GSDMD-deficient mice show a less severe F. novicida infection than caspase-1-deficient mice. 96 Intriguingly, the mechanism of IL-1 maturation itself empowers its relocation from the cytosol to the phosphatidylinositol 4,5bisphosphate microdomains in the plasma membrane. This effect enables fast exit of IL-1 via GSDMD pore or its slow secretion in a GSDMD-independent manner.…”