Microbial Pathogen-Induced Necrotic Cell Death Mediated by the Inflammasome Components CIAS1/Cryopyrin/NLRP3 and ASC

Abstract

Cryopyrin (CIAS1, NLRP3) and ASC are components of the inflammasome, a multiprotein complex required for caspase-1 activation and cytokine IL-1beta production. CIAS1 mutations underlie autoinflammation characterized by excessive IL-1beta secretion. Disease-associated cryopyrin also causes a program of necrosis-like cell death in macrophages, the mechanistic details of which are unknown. We find that patient monocytes carrying disease-associated CIAS1 mutations exhibit excessive necrosis-like death by a process dependent on ASC and cathepsin B, resulting in spillage of the proinflammatory mediator HMGB1. Shigella flexneri infection also causes cryopyrin-dependent macrophage necrosis with features similar to the death caused by mutant CIAS1. This necrotic death is independent of caspase-1 and IL-1beta, and thus independent of the inflammasome. Furthermore, necrosis of primary macrophages requires the presence of Shigella virulence genes. While similar proteins mediate pathogen-induced cell death in plants, this report identifies cryopyrin as an important host regulator of programmed pathogen-induced necrosis in animals, a process we term pyronecrosis.

Shigella IpaH7.8 E3 ubiquitin ligase targets glomulin and activates inflammasomes to demolish macrophages

“…In the case of Shigella, the bacteria rapidly induce macrophage cell death at early stages of infection, which is accompanied by NLR inflammasome activation and inflammatory cell death through a T3SS-dependent mechanism (19,22). Previous studies indicated that during replication in macrophages, LPS, peptidoglycan, and T3SS rod or needle components of Shigella are recognized by the NLRC4 and NLRP3 inflammasomes (8,(19)(20)(21). Interestingly, the mode through which NLRs recognize Shigella infections seems to vary across different infection conditions.…”

Cell death in the host response to infection

“…90 However, at higher MOI, Shigella induces a caspase-1-independent form of cell death termed pyronecrosis. 104 Diseaseassociated cryopyrin appears to trigger this death mode as well, which is independent of caspase-1 but presumably requires cathepsin B. 104 The IPAF-caspase-1 inflammasome has been recently shown to be essential for the initiation of a proper innate immune response to Pseudomonas aeruginosa.…”

“…104 Diseaseassociated cryopyrin appears to trigger this death mode as well, which is independent of caspase-1 but presumably requires cathepsin B. 104 The IPAF-caspase-1 inflammasome has been recently shown to be essential for the initiation of a proper innate immune response to Pseudomonas aeruginosa. 51,91 Virulent P. aeruginosa isolates that evade the immune response express the effector protein exoenzyme U (ExoU).…”

Lysosomes in programmed cell death pathways: from initiators to amplifiers

“…Also in these cases, inhibition of cathepsin B, and possibly other proteases, by CA-074-Me attenuated cell death and limited inflammatory cytokine release (Willingham et al, 2007;Duncan et al, 2009). This further suggests that inducers of pyrogenic cell death, including lysosome-destabilizing agents, trigger different cellular events, which importantly rely on the extent and timing of LMP.…”