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 inhibi-tion via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-10 (IL-10) 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 be-came prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-10/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced sep-tic 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-10 produc-tion. Therefore, the autophagy and cathepsin-B axis represents one of the pathways leading to atypical inflam-masome activation when apoptosis and necroptosis are suppressed and capase-8 is inhibited in myeloid cells.

Automated summary

Inhibition of Caspase-8 leads to inflammasome assembly and production of IL-10 and IL-18 in Toll-like receptor (TLR)-primed myeloid cells. Autophagy and cathepsin-B play important roles in the activation of inflammasomes when apoptosis and necroptosis are blocked and Caspase-8 is inhibited.