Enhanced Susceptibility to Chemically Induced Colitis Caused by Excessive Endosomal TLR Signaling in LRBA-deficient Mice

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2019 May 18

PMID 31097594

Citations 13

Authors

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

Affiliations

Soon will be listed here.

Abstract

LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (T) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen for -ethyl--nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in Although T 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. 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 , 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.

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