XIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death
Axel Witt1,2, Tatiana Goncharov1, Yujung Michelle Lee1
1Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA.
Abstract:
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.
Insights
X-linked inhibitor of apoptosis protein (XIAP) deficiency worsens inflammatory disease prognosis. Its absence sensitizes to cell death, but RIP1 inhibition rescues TNF-mediated inflammation, offering a potential therapeutic target.
Area of Science:
- Cellular Biology
- Immunology
- Molecular Medicine
Background:
- X-linked inhibitor of apoptosis protein (XIAP) is crucial for blocking cell death pathways and regulating inflammatory signaling.
- XIAP deficiency is linked to poorer outcomes in inflammatory diseases and hematopoietic cell transplantation.
- Understanding XIAP's role in inflammation is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of XIAP in lipopolysaccharide (LPS)- and tumor necrosis factor (TNF)-mediated cell death and inflammation.
- To determine the specific signaling pathways involved in XIAP-deficient inflammatory responses.
- To evaluate the therapeutic potential of targeting RIP kinases in XIAP deficiency.
Main Methods:
- Utilized cell and mouse models with XIAP deficiency.
- Assessed sensitivity to LPS- and TNF-induced cell death.
- Analyzed NF-κB and MAPK signaling pathways.
- Investigated the effects of RIP1 and RIP2 inhibition on TNF-stimulated responses.
Main Results:
- XIAP absence sensitizes cells and mice to LPS- and TNF-induced cell death, independent of NF-κB and MAPK signaling.
- RIP1 inhibition effectively ameliorates TNF-stimulated cell death, hypothermia, lethality, cytokine release, tissue damage, and granulocyte migration in XIAP-deficient mice.
- RIP2 inhibition showed no significant effect on TNF-stimulated events, indicating the RIP2-NOD2 pathway is not involved.
Conclusions:
- XIAP deficiency exacerbates TNF-mediated inflammation by implicating RIP1 as a critical mediator.
- RIP1 inhibition presents a promising therapeutic strategy for managing inflammatory conditions in patients with XIAP deficiency.
- The findings highlight a novel therapeutic avenue for inflammatory diseases associated with XIAP deficiency.
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