| Autor: |
Wu YH; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan., Mo ST; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan., Chen IT; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan., Hsieh FY; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan., Hsieh SL; Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan., Zhang J; Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA., Lai MZ; Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan. |
| Abstrakt: |
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. |
