Control of Dendritic Cell Function by the Lipopolysaccharide (LPS)-Responsive and Beige-like Anchor protein (Lrba)

点击翻译按钮获取中文摘要

Project Summary LRBA protein deficiency is a monogenic cause of autoimmunity and inflammatory bowel disease (IBD) in humans, but the basic cellular and molecular underpinnings responsible for the disease are not completely 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. We found that dendritic cells (DCs) contribute significantly to intestinal inflammation in Lrba- deficient mice. In response to the stimulation of the Toll-like receptors (TLRs) TLR3, TLR7, and TLR9, Lrba- /- DCs exhibited excessive chemokine and type I interferon production as well as exaggerated IRF3/7- and PI3K/mTORC1-dependent signaling. Knockout of Unc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes, caused a significant amelioration of the cytokine expression and colitis sensitivity after DSS treatment in Lrba-/- mice. Our data support a function for Lrba in restricting endosomal TLR signaling and subsequent intestinal inflammation. We propose to further elucidate the role of Lrba in innate immune cells in two interconnected and focused aims: Aim 1: To determine the role dendritic cell-intrinsic Lrba plays in experimental colitis. Aim 2: Elucidate the cellular trafficking defects of Lrba-/- dendritic cells that lead to exaggerated endosomal TLR responses. The aims in this proposal will help elucidate the mechanisms underlying the role of dendritic cells in tissue inflammation and the coordination of immune signaling within them.