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

Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11380-11389. doi: 10.1073/pnas.1901407116. Epub 2019 May 16.

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-N-nitrosourea (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.

Keywords: IRF3; IRF7; Toll-like receptor; dendritic cells; inflammatory bowel disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Autoimmunity / physiology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / metabolism
  • Colitis / chemically induced
  • Colitis / metabolism*
  • Cytokines / metabolism
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Dextran Sulfate / pharmacology
  • Endosomes / metabolism*
  • Female
  • Inflammation / metabolism
  • Male
  • Membrane Transport Proteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Molecular Chaperones / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / metabolism*

Substances

  • Adaptor Proteins, Signal Transducing
  • Cytokines
  • Membrane Transport Proteins
  • Molecular Chaperones
  • Dextran Sulfate
  • Lrba protein, mouse