Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice

Kuan Wen Wang, Xiaoming Zhan, William McAlpine, Zhao Zhang, Jin Huk Choi, Hexin Shi, Takuma Misawa, Tao Yue, Duanwu Zhang, Ying Wang, Sara Ludwig, Jamie Russell, Miao Tang, Xiaohong Li, Anne R. Murray, Eva Marie Y. Moresco, Emre E. Turer, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen for N-ethyl-Nnitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Lrba. Although Treg cells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice. Lrba-/- DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.

Original languageEnglish (US)
Pages (from-to)11380-11389
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume166
Issue number23
DOIs
StatePublished - 2019

Keywords

  • Dendritic cells
  • IRF3
  • IRF7
  • Inflammatory bowel disease
  • Toll-like receptor

ASJC Scopus subject areas

  • General

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