LRBA Restricts Murine Colitis by Regulating Interferon Responses and Autophagy

Lrba encodes lipopolysaccharide-responsive and beige like anchor (LRBA) protein, which was originally identified as an LPS-inducible gene in immune cells. LRBA putatively regulates the recycling and degradation of proteins critical for immune quiescence in human lymphocytes. However, recent studies showed that Lrba-deficient rodents had normal adaptive immune responses. Mutations in Lrba are associated with the immune deficiency, autoimmunity, and inflammatory bowel diseases (IBDs) in human; however it is unclear how LRBA regulates intestinal homeostasis and the cellular mechanisms it involves in. Here, I showed that LRBA is critical for both adaptive and innate immunity by regulating T cell, dendritic cells and intestinal epithelial cells to control inflammation. Lrba-deficient (Lrba-/-) mice showed a murine model colitis-DSS-induced colitis, and LRBA expression was essential in the hematopoietic (in both adaptive and non-adaptive) and non-hematopoietic compartment to prevent colitis susceptibility. LRBA regulates T cell homeostasis and activation, and Lrba-/- T cells skew to more effector subsets, especially Th1 and Th17 condition, but not to naïve and regulatory subsets (naïve T and regulatory T cells) in splenocytes and colon lamina propria lymphocytes. Furthermore, Lrba-/- naïve T cells showed a greater potential to become activated, lead to intestinal inflammation. Moreover, the possible mechanism that LRBA regulates T cell function is through PI3K/AKT/mTOR signaling. Bone marrow-derived dendritic cells (BMDCs) from Lrba-/- mice contribute to intestinal inflammation in an adaptive immune cells-independent manner. Lrba-/- BMDCs displayed an accumulated endosomal Toll-like receptor (TLR) ligands in the lysosomes, and led to excessive interferons (IFNs) signaling in response to endosomal TLR stimulation through IRF3/7 pathway that was PI3K/AKT/mTOR pathway-dependent. Furthermore, blocking the endosomal TLRs translocation to endolysosome/lysosome by genetically disturbs UNC93B1 to reduce enhanced IFN signaling that partially ameliorated the experimentally-induced colitis severity. Accumulated autophagosomes was observed in both BMDCs and intestinal epithelial cells in LRBA deficient condition. The possibly impaired autophagosome-lysosome fusion led to the defect of autophagy might be the reason for accumulated autophagosomes, further exaggerated a potential intracellular cell stress from dysfunctional organelles to dampen the inflammation from the dysregulated endosomal TLR signaling. Taking together, the possibility of LRBA functions in the process of vesicle fusion (endosome-autophagosome-lysosome) that suggests LRBA could be as a new potential linker between innate endosomal TLR signaling, adaptive immune functions and autophagy. Therefore, deficiency of LRBA can lead to excessive inflammatory responses and induction of colitis.