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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 23; pp. 11380 - 11389
• Main Authors: Wang, Kuan-wen, Zhan, Xiaoming, McAlpine, William, Zhang, Zhao, Choi, Jin Huk, Shi, Hexin, Misawa, Takuma, Yue, Tao, Zhang, Duanwu, Wang, Ying, Ludwig, Sara, Russell, Jamie, Tang, Miao, Li, Xiaohong, Murray, Anne R., Moresco, Eva Marie Y., Turer, Emre E., Beutler, Bruce
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04.06.2019
• Series: PNAS Plus
• Subjects: 1-Phosphatidylinositol 3-kinase; Adaptor Proteins, Signal Transducing - metabolism; Animals; Autoimmune diseases; Autoimmunity; Autoimmunity - physiology; B-Lymphocytes - drug effects; B-Lymphocytes - metabolism; Biological Sciences; Colitis; Colitis - chemically induced; Colitis - metabolism; Colon; Cytokines - metabolism; Defects; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Dextran; Dextran Sulfate - pharmacology; Endosomes; Endosomes - metabolism; Ethyl nitrosourea; Female; Genetic screening; Hypogammaglobulinemia; Immune system; Inflammation - metabolism; Inflammatory bowel disease; Inflammatory bowel diseases; Interferon; Interferon regulatory factor 3; Intestine; Lipopolysaccharides; Lymphocytes B; Lymphocytes T; Male; Membrane Transport Proteins - metabolism; Mice; Mice, Inbred C57BL; Molecular Chaperones - metabolism; Molecular modelling; Mutation; Organic chemistry; PNAS Plus; Protein deficiency; Proteins; Receptors; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; Sodium; Sodium sulfate; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; TLR3 protein; TLR7 protein; TLR9 protein; Toll-like receptors; IRF7; dendritic cells; IRF3; Toll-like receptor; inflammatory bowel disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1901407116

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.