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^-/- 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.