Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo.
dc.contributor.author | Reinke, Sören | |
dc.contributor.author | Linge, Mary | |
dc.contributor.author | Diebner, Hans H | |
dc.contributor.author | Luksch, Hella | |
dc.contributor.author | Glage, Silke | |
dc.contributor.author | Gocht, Anne | |
dc.contributor.author | Robertson, Avril A B | |
dc.contributor.author | Cooper, Matthew A | |
dc.contributor.author | Hofmann, Sigrun R | |
dc.contributor.author | Naumann, Ronald | |
dc.contributor.author | Sarov, Mihail | |
dc.contributor.author | Behrendt, Rayk | |
dc.contributor.author | Roers, Axel | |
dc.contributor.author | Pessler, Frank | |
dc.contributor.author | Roesler, Joachim | |
dc.contributor.author | Rösen-Wolff, Angela | |
dc.contributor.author | Winkler, Stefan | |
dc.date.accessioned | 2020-03-13T09:15:40Z | |
dc.date.available | 2020-03-13T09:15:40Z | |
dc.identifier.citation | Cell Rep. 2020 Feb 25;30(8):2501-2511.e5. doi: 10.1016/j.celrep.2020.01.090. | en_US |
dc.identifier.pmid | 32101731 | |
dc.identifier.doi | 10.1016/j.celrep.2020.01.090 | |
dc.identifier.uri | http://hdl.handle.net/10033/622203 | |
dc.description.abstract | Pro-inflammatory caspase-1 is a key player in innate immunity. Caspase-1 processes interleukin (IL)-1β 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-1β production. In vitro data suggest that enzymatically inactive caspase-1 drives inflammation via enhanced nuclear factor κB (NF-κB) activation, independent of IL-1β 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-α) and IL-6 when challenged with lipopolysaccharide (LPS). Caspase-1-C284A signaling is RIP2 dependent and mediated by TNF-α 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-α. Taken together, these results reveal non-canonical caspase-1 signaling in vivo. | en_US |
dc.language.iso | en | en_US |
dc.publisher | Elsevier/ Cell Press | en_US |
dc.rights | Attribution-NonCommercial-ShareAlike 4.0 International | * |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | NF-κB | en_US |
dc.subject | Rip2 | en_US |
dc.subject | TNF-α | en_US |
dc.subject | caspase-1 | en_US |
dc.subject | enzymatic activity | en_US |
dc.subject | non-canonical caspase-1 signaling | en_US |
dc.title | Non-canonical Caspase-1 Signaling Drives RIP2-Dependent and TNF-α-Mediated Inflammation In Vivo. | en_US |
dc.type | Article | en_US |
dc.identifier.eissn | 2211-1247 | |
dc.contributor.department | TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany. | en_US |
dc.identifier.journal | Cell reports | en_US |
dc.source.volume | 30 | |
dc.source.issue | 8 | |
dc.source.beginpage | 2501 | |
dc.source.endpage | 2511.e5 | |
refterms.dateFOA | 2020-03-13T09:15:42Z | |
dc.source.journaltitle | Cell reports | |
dc.source.country | United States |