Caspase‐8‐driven apoptotic and pyroptotic crosstalk causes cell death and IL‐1β release in X‐linked inhibitor of apoptosis (XIAP) deficiency

Abstract

Genetic lesions in X‐linked inhibitor of apoptosis (XIAP) pre‐dispose humans to cell death–associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that two patients with XIAP deficiency–associated inflammatory bowel disease display increased inflammatory IL‐1β maturation as well as cell death–associated caspase‐8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase‐8‐driven cell death and bioactive IL‐1β release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase‐8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase‐1, ‐3, ‐7, ‐11 and BID), while caspase‐8 can still cause cell death in the absence of both GSDMD and GSDME when caspase‐3 and caspase‐7 are present. Neither caspase‐3 and caspase‐7‐mediated activation of the pannexin‐1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase‐1 and IL‐1β maturation downstream of XIAP inhibition and caspase‐8 activation, even though the pannexin‐1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co‐opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.

NLRP3 selectively drives IL-1β secretion by Pseudomonas aeruginosa infected neutrophils and regulates corneal disease severity

“…Notably, the PAO1-induced accumulation of cleaved GSDME in neutrophils was not inhibited by ZVAD. Lien et al and Poltorak et al showed that caspase-8 mediates GSDMD processing in Yersinia infected macrophages 27 , 28 , and Vince et al 29 recently reported that caspase-8 is associated with GSDMD cleavage in macrophages from patients with mutations in the X-linked inhibitor of apoptosis protein (XIAP) and in murine macrophages incubated with IAP antagonists. However, although caspase-8 was cleaved in TNF/SM treated macrophages and neutrophils, caspase-8 was not cleaved following PAO1 infection (Fig.…”

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…Its functional role depends on the interplay with other partners, and even subtle alterations in the composition of caspase-8 complexes can give rise to contradicting physiological outcomes, such as the switching between macrophage death modalities or between cell death and cell activation ( 119 ). Notably, in the absence of an X‐linked inhibitor of apoptosis (XIAP), extrinsic caspase-8 promotes pyroptotic GSDMD processing, resulting in the demise of macrophages lacking both inflammasome and apoptosis signaling components (caspase-1, -3, -7, -11 and BID) ( 124 ). In addition to RIPK1, caspase-8 can cleave RIPK3 ( 125 ).…”

Targeting regulated cell death pathways in acute myeloid leukemia

“…Other examples of cross-talk between RCD include the link between ferroptosis and autophagy, in particular through ferritin degradation or the involvement of lysosomes in iron storage and redistribution [47,48] . Depletion of the ferroptosis trigger GPX4 also sensitizes cells to pyroptosis [49] , necroptosis [50] and apoptosis [51] . Apoptosis and necroptosis are also linked through caspase 8 cleavage [Figure 1].…”

“…Apoptosis and necroptosis are also linked through caspase 8 cleavage [ Figure 1 ]. Caspase 8 is also an important player in pyroptosis induction, as it has been shown that genetic lesions in XIAP result in increased inflammation and death-associated caspase-8 and GSDMD processing in diseased tissue [ 52 ] . Common stimuli can also result in different RCD depending on the cell type.…”