| First Author | Wu YH | Year | 2022 |
| Journal | Sci Adv | Volume | 8 |
| Issue | 45 | Pages | eabn9912 |
| PubMed ID | 36367942 | Mgi Jnum | J:359970 |
| Mgi Id | MGI:7387697 | Doi | 10.1126/sciadv.abn9912 |
| Citation | Wu YH, et al. (2022) Caspase-8 inactivation drives autophagy-dependent inflammasome activation in myeloid cells. Sci Adv 8(45):eabn9912 |
| abstractText | 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-1beta (IL-1beta) 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-1beta/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-1beta 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. |
