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.
Wu, Yung-Hsuan; Mo, Shu-Ting; Chen, I-Ting; Hsieh, Fu-Yi; Hsieh, Shie-Liang; Zhang, Jianke; and Lai, Ming-Zong, "Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells." (2022). Department of Microbiology and Immunology Faculty Papers. Paper 168.
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This is the final published article from the journal Science Advances, 2022 Nov 11;8(45):eabn9912.
The article is also available on the journal's website: https://doi.org/10.1126/sciadv.abn9912.
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