XIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death.

Autor: Witt A; Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA.; Neovii Pharmaceutical AG, 8640, Rapperswil, Switzerland., Goncharov T; Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA., Lee YM; Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA., Kist M; Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA.; CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany., Dohse M; Department of Pathology, Genentech, South San Francisco, CA, 94080, USA., Eastham J; Department of Pathology, Genentech, South San Francisco, CA, 94080, USA., Dugger D; Department of Physiological Chemistry, Genentech, South San Francisco, CA, 94080, USA., Newton K; Department of Physiological Chemistry, Genentech, South San Francisco, CA, 94080, USA., Webster JD; Department of Pathology, Genentech, South San Francisco, CA, 94080, USA., Vucic D; Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA. domagoj@gene.com.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2023 Apr 11; Vol. 14 (4), pp. 262. Date of Electronic Publication: 2023 Apr 11.
DOI: 10.1038/s41419-023-05793-1
Abstrakt: XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn's disease, or those needing allogeneic hematopoietic cell transplantation, is associated with a worse prognosis. In this study, we show that XIAP absence sensitizes cells and mice to LPS- and TNF-mediated cell death without affecting LPS- or TNF-induced NF-κB and MAPK signaling. In XIAP deficient mice, RIP1 inhibition effectively blocks TNF-stimulated cell death, hypothermia, lethality, cytokine/chemokine release, intestinal tissue damage and granulocyte migration. By contrast, inhibition of the related kinase RIP2 does not affect TNF-stimulated events, suggesting a lack of involvement for the RIP2-NOD2 signaling pathway. Overall, our data indicate that in XIAP's absence RIP1 is a critical component of TNF-mediated inflammation, suggesting that RIP1 inhibition could be an attractive option for patients with XIAP deficiency.
(© 2023. The Author(s).)
Databáze: MEDLINE
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