| First Author | Reinke S | Year | 2020 |
| Journal | Cell Rep | Volume | 30 |
| Issue | 8 | Pages | 2501-2511.e5 |
| PubMed ID | 32101731 | Mgi Jnum | J:288227 |
| Mgi Id | MGI:6416052 | Doi | 10.1016/j.celrep.2020.01.090 |
| Citation | Reinke S, et al. (2020) Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-alpha-Mediated Inflammation In Vivo. Cell Rep 30(8):2501-2511.e5 |
| abstractText | Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1beta and IL-18 to their mature forms and triggers pyroptosis. These caspase-1 functions are linked to its enzymatic activity. However, loss-of-function missense mutations in CASP1 do not prevent autoinflammation in patients, despite decreased IL-1beta production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor kappaB (NF-kappaB) activation, independent of IL-1beta processing. Here, we report two mouse models of enzymatically inactive caspase-1-C284A, demonstrating the relevance of this pathway in vivo. In contrast to Casp1(-/-) mice, caspase-1-C284A mice show pronounced hypothermia and increased levels of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-alpha but independent of the NLRP3 inflammasome. LPS-stimulated whole blood from patients carrying loss-of-function missense mutations in CASP1 secretes higher amounts of TNF-alpha. Taken together, these results reveal non-canonical caspase-1 signaling in vivo. |
