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, He-Xin Shi, Takuma Misawa, Tao Yue, Duan-Wu Zhang Ph.D., Ying Wang, Sara Ludwig, Jamie L Russell, Miao Tang, Xiaohong Li, Anne R. Murray, Eva Marie Y. Moresco, Emre E Turer, Bruce A Beutler

Research output: Contribution to journalArticle

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 - Jan 1 2019

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Dextran Sulfate
Toll-Like Receptors
Regulatory T-Lymphocytes
Colitis
Dendritic Cells
Toll-Like Receptor 3
Inflammation
Protein Deficiency
Agammaglobulinemia
Nonsense Codon
Endosomes
Autoimmunity
Phosphatidylinositol 3-Kinases
Inflammatory Bowel Diseases
B-Lymphocytes
Cytokines
Mutation
Research

Keywords

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

ASJC Scopus subject areas

  • General

Cite this

Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice. / Wang, Kuan Wen; Zhan, Xiaoming; McAlpine, William; Zhang, Zhao; Choi, Jin Huk; Shi, He-Xin; Misawa, Takuma; Yue, Tao; Zhang Ph.D., Duan-Wu; Wang, Ying; Ludwig, Sara; Russell, Jamie L; Tang, Miao; Li, Xiaohong; Murray, Anne R.; Moresco, Eva Marie Y.; Turer, Emre E; Beutler, Bruce A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 166, No. 23, 01.01.2019, p. 11380-11389.

Research output: Contribution to journalArticle

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AU - Shi, He-Xin

AU - Misawa, Takuma

AU - Yue, Tao

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AU - Ludwig, Sara

AU - Russell, Jamie L

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AU - Beutler, Bruce A

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