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  Deficiency in X-linked inhibitor of apoptosis protein promotes susceptibility to microbial triggers of intestinal inflammation

Strigli, A., Gopalakrishnan, S., Zeissig, Y., Basic, M., Wang, J., Schwerd, T., et al. (2021). Deficiency in X-linked inhibitor of apoptosis protein promotes susceptibility to microbial triggers of intestinal inflammation. Science Immunology, 6(65): eabf7473. doi:10.1126/sciimmunol.abf7473.

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 Creators:
Strigli, Anne, Author
Gopalakrishnan, Shreya, Author
Zeissig, Yvonne, Author
Basic, Marijana, Author
Wang, Jun1, Author           
Schwerd, Tobias, Author
Doms, Shauni1, Author           
Peuker, Kenneth, Author
Hartwig, Jelka, Author
Harder, Jürgen, Author
Hönscheid, Pia, Author
Arnold, Philipp, Author
Kurth, Thomas, Author
Rost, Fabian, Author
Petersen, Britt-Sabina, Author
Forster, Michael, Author
Franke, Andre, Author
Kelsen, Judith R., Author
Rohlfs, Meino, Author
Klein, Christoph, Author
Muise, Aleixo M., AuthorWarner, Neil, AuthorNambu, Ryusuke, AuthorMayerle, Julia, AuthorTörök, Helga-Paula, AuthorLinkermann, Andreas, AuthorMuders, Michael H., AuthorBaretton, Gustavo B., AuthorHampe, Jochen, AuthorAust, Daniela E., AuthorBaines, John F.1, Author           Bleich, André, AuthorZeissig, Sebastian, Author more..
Affiliations:
1Guest Group Evolutionary Medicine (Baines), Max Planck Institute for Evolutionary Biology, Max Planck Society, ou_3371474              

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 Abstract: Deficiency in XIAP is associated with Paneth cell defects and susceptibility to microbiota-dependent intestinal inflammation. Genetic variations, especially in Paneth cells, contribute to inflammatory bowel disease (IBD). X-linked inhibitor of apoptosis protein (XIAP) alterations are commonly associated with IBD, but how XIAP deficiency regulates Paneth cells is unclear. Here, Strigli et al. used XIAPKO mice and organoids to determine how XIAP alters IBD. They found that XIAP deficiency (mice and patient samples) made Paneth cells sensitive to cell death induced by microbiota, TNF, and RIPK1/3. Specifically, loss of Paneth cell–derived antimicrobial peptides led to microbiota alterations in the XIAPKO mice, making mice more susceptible to IBD. Last, IBD could be inhibited in XIAPKO mice by administration of antimicrobial peptides, pointing to a potential therapy that could be used for IBD associated with Paneth cell loss. Inflammatory bowel disease (IBD) is characterized by inappropriate immune responses to the microbiota in genetically susceptible hosts, but little is known about the pathways that link individual genetic alterations to microbiota-dependent inflammation. Here, we demonstrated that the loss of X-linked inhibitor of apoptosis protein (XIAP), a gene associated with Mendelian IBD, rendered Paneth cells sensitive to microbiota-, tumor necrosis factor (TNF)–, receptor-interacting protein kinase 1 (RIPK1)–, and RIPK3-dependent cell death. This was associated with deficiency in Paneth cell–derived antimicrobial peptides and alterations in the stratification and composition of the microbiota. Loss of XIAP was not sufficient to elicit intestinal inflammation but provided susceptibility to pathobionts able to promote granulomatous ileitis, which could be prevented by administration of a Paneth cell–derived antimicrobial peptide. These data reveal a pathway critical for host-microbial cross-talk, which is required for intestinal homeostasis and the prevention of inflammation and which is amenable to therapeutic targeting.

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Language(s): eng - English
 Dates: 2021-07-232020-11-172021-09-132021-11-052021-11
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1126/sciimmunol.abf7473
 Degree: -

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Title: Science Immunology
  Abbreviation : Sci Immunol.
Source Genre: Journal
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Publ. Info: Washington, DC : American Association for the Advancement of Science
Pages: - Volume / Issue: 6 (65) Sequence Number: eabf7473 Start / End Page: - Identifier: ISSN: 2470-9468
CoNE: https://pure.mpg.de/cone/journals/resource/2470-9468