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

  • Sci Adv. 2022 Nov 11;8(45):eabn9912. doi: 10.1126/sciadv.abn9912.
Yung-Hsuan Wu  1 ,  Shu-Ting Mo  1 ,  I-Ting Chen  1 ,  Fu-Yi Hsieh  1 ,  Shie-Liang Hsieh  2 ,  Jinake Zhang  3 ,  Ming-Zong Lai  1
Affiliations
  • 1. Institute of Molecular Biology, Academia Sinica, Taipei 11529, Taiwan.
  • 2. Genomic Research Center, Academia Sinica, Taipei 11529, Taiwan.
  • 3. Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
PMID: 36367942 DOI: 10.1126/sciadv.abn9912
Abstract

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.

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