biostudies-literatureUnknown14(4)Witt AXIAP 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 invoCell death & disease262https://www.ebi.ac.uk/biostudies/studies/S-EPMC10090100biostudies-literatureXIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death.PMC10090100Witt AVucic DWebster JDKist MDugger DLee YMNewton KEastham JDohse MGoncharov TfalseXIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death.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 invo2023-01-01T00:00:00Z2023 Apr2025-04-04T12:01:38.267Z2025-04-04T12:01:38.267ZS-EPMC100901003704117510.1038/s41419-023-05793-1