TY - JOUR
T1 - Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice
AU - Wang, Kuan Wen
AU - Zhan, Xiaoming
AU - McAlpine, William
AU - Zhang, Zhao
AU - Choi, Jin Huk
AU - Shi, Hexin
AU - Misawa, Takuma
AU - Yue, Tao
AU - Zhang Ph.D., Duan-Wu
AU - Wang, Ying
AU - Ludwig, Sara
AU - Russell, Jamie
AU - Tang, Miao
AU - Li, Xiaohong
AU - Murray, Anne R.
AU - Moresco, Eva Marie Y.
AU - Turer, Emre E.
AU - Beutler, Bruce
N1 - Funding Information:
ACKNOWLEDGMENTS. This work was supported by the National Institutes of Health Grants AI125581 (to B.B.) and DK107886 and AI095542 (to E.E.T.), Immunology T32 Training Grant AI005184 (to W.M.), and by the Lyda Hill Foundation.
Publisher Copyright:
© 2019 National Academy of Sciences. All rights reserved.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Dendritic cells
KW - IRF3
KW - IRF7
KW - Inflammatory bowel disease
KW - Toll-like receptor
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U2 - 10.1073/pnas.1901407116
DO - 10.1073/pnas.1901407116
M3 - Article
C2 - 31097594
AN - SCOPUS:85066791708
VL - 166
SP - 11380
EP - 11389
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 23
ER -