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, Doms S, Peuker K, Hartwig J, Harder J, Hoenscheid P, Arnold P, Kurth T, Rost F, Petersen BS, Forster M, Franke A, Kelsen JR, Rohlfs M, Klein C, Muise AM, Warner N, Nambu R, Mayerle J, Toeroek HP, Linkermann A, Muders MH, Baretton GB, Hampe J, Aust D, Baines JF, Bleich A, Zeissig S (2021)

Publication Type: Journal article

Publication year: 2021

Journal

Science immunology American Association for the Advancement of Science

Book Volume: 6

Journal Issue: 65

DOI: 10.1126/sciimmunol.abf7473

Abstract

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 microbiotadependent 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.

Authors with CRIS profile

Philipp Arnold Lehrstuhl für Funktionelle und Klinische Anatomie

Involved external institutions

Technische Universität Dresden DE Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School DE Germany (DE) Max-Planck-Institut für Evolutionsbiologie / Max Planck Institute for Evolutionary Biology DE Germany (DE) Ludwig-Maximilians-Universität (LMU) DE Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Christian-Albrechts-Universität zu Kiel DE Germany (DE) University of Pennsylvania (UPenn) US United States (USA) (US) The Hospital for Sick Children (SickKids) CA Canada (CA)

How to cite

APA:

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

MLA:

Strigli, Anne, et al. "Deficiency in X-linked inhibitor of apoptosis protein promotes susceptibility to microbial triggers of intestinal inflammation." Science immunology 6.65 (2021).

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