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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

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 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.

Details

Original languageEnglish
Article numbereabf7473
Pages (from-to)eabf7473
JournalScience immunology
Volume6
Issue number65
Publication statusPublished - 5 Nov 2021
Peer-reviewedYes

External IDs

Scopus 85120302920
ORCID /0000-0001-6466-2589/work/142238090
ORCID /0000-0001-5624-1717/work/142239003
ORCID /0000-0001-6287-9725/work/142251579

Keywords

Keywords

  • Animals, Antimicrobial Peptides/administration & dosage, Female, Humans, Inflammation/drug therapy, Inhibitor of Apoptosis Proteins/deficiency, Intestines/drug effects, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microbiota/drug effects, Paneth Cells/chemistry, X-Linked Inhibitor of Apoptosis Protein/deficiency

Library keywords