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

Dr. Lai, Ming-Zong - November, 2022

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, a critical step in suppressing intracellular viral replication with unknown mechanism. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted inflammasome activation and pyroptosis induction. Caspase-8, caspase-1/11 and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for caspase-8-inactivation-triggered inflammasome activation. Autophagy became prominent in these myeloid cells, followed by cathepsin-B activation, and inhibiting autophagy or cathepsin-B limited inflammasome activation and pyroptosis. Therefore, the switch to autophagy and cathepsin-B axis turns on atypical inflammasome activation in myeloid cells deficient in apoptosis and necroptosis, unveiling a new stage for pyroptosis generation during development and pathogen infection.