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

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.

Environmental and genetic disease modifiers of haploinsufficiency of A20

“…The experimental approaches deployed here possess real potential in the study of both HA20 and polygenic inflammatory bowel disease (IBD). The failure of mouse avatars representing the genetics of human monogenic inflammatory disease to express a clinical phenotype unless specifically challenged is not unique, with Lrba gene-deficient animals requiring DSS stimulation to develop clinical disease (62). The models of colitis presented here associated with mice having a more ‘wild-type’ intestinal flora contributes to growing knowledge for human IBD where the search for pathogenic mechanisms is increasingly focused on changes to the intestinal microbiota (63).…”

Essential requirement for nicastrin in marginal zone and B-1 B cell development

“…DSS-Induced Colitis Screen. For DSS-induced colitis induction (36,000 to 50,000 molecular weight; MP Biomedicals), 8-to 12-wk-old mice received 1.3% DSS in the drinking water for 7 d, followed by 3 d off DSS, as described previously (41). Body weight was recorded daily and reported as a percentage relative to the pretreatment body weight.…”

Immune checkpoint deficiencies and autoimmune lymphoproliferative syndromes

“…However, in 2019 Wang et al. reported that LRBA-null mice had an enhanced susceptibility to DSS-induced colitis [ 66 ]. Interestingly, they conclude that the excessive intestinal inflammation of LRBA-null mice to DSS was caused by a hyperactivation of the endosomal TLR signaling, resulting in increased expression of IRF3/7-dependent genes such as IL-8, CXCL10, RANTES and CCL3, as well as an elevated IL-23 in response to endosomal TLR stimulation.…”

“…murine LRBA-deficient NK cells exhibited impaired signalling by the key NK activating receptors, NKp46 and NKG2D, which interact with ligands expressed on the surface of virally infected, stressed or malignant cell targets [ 67 ]. This abnormality might result in the inability to respond to viruses but also in the inability to reject allogenic BM grafts, making LRBA-deficient patients highly susceptible to tumors and viral infections but good candidates for HSCT due to their possible resistance to acute GvHD as observed in LRBA-null mice [ 66 ]. However, according to the published LRBA deficiency cohorts, patients do not show susceptibility to any specific microorganism or virus.…”