Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells

Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)–primed Fadd −/− Ripk3 −/− my...

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Bibliographic Details
Published in:Science advances Vol. 8; no. 45; p. eabn9912
Main Authors: Wu, Yung-Hsuan, Mo, Shu-Ting, Chen, I-Ting, Hsieh, Fu-Yi, Hsieh, Shie-Liang, Zhang, Jinake, Lai, Ming-Zong
Format: Journal Article
Language:English
Published: American Association for the Advancement of Science 11-11-2022
Subjects:
Biomedicine and Life Sciences
Cell Biology
Immunology
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Summary:Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)–primed Fadd −/− Ripk3 −/− myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd −/− Ripk3 −/− macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic shock in Fadd −/− Ripk3 −/− mice, implying distinct death processes in other cell types. Cathepsin-B contributes to IETD-mediated inflammasome activation, as its inhibition or down-regulation limited IETD-elicited IL-1β production. Therefore, the autophagy and cathepsin-B axis represents one of the pathways leading to atypical inflammasome activation when apoptosis and necroptosis are suppressed and capase-8 is inhibited in myeloid cells. Caspase-8 inactivation in apoptosis/necroptosis-null myeloid cells induces inflammasome activation via autophagy/cathepsin-B.
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ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abn9912