Format

Send to

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

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505.
2
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505; Emre.Turer@UTSouthwestern.edu Bruce.Beutler@UTSouthwestern.edu.
3
Department of Internal Medicine, Division of Gastroenterology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505.

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

PMID:
31097594
PMCID:
PMC6561264
[Available on 2019-11-16]
DOI:
10.1073/pnas.1901407116

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center