2019年6月4日
Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice
Proceedings of the National Academy of Sciences
- 巻
- 116
- 号
- 23
- 開始ページ
- 11380
- 終了ページ
- 11389
- 記述言語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1073/pnas.1901407116
- 出版者・発行元
- Proceedings of the National Academy of Sciences
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 <italic>N</italic>-ethyl-<italic>N</italic>-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations in <italic>Lrba</italic>. 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. <italic>Lrba</italic><italic>−/−</italic> 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 <italic>Unc93b1</italic>, 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.
- リンク情報
- ID情報
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- DOI : 10.1073/pnas.1901407116
- ISSN : 0027-8424
- eISSN : 1091-6490