#Left 4 dead 2 g2a Activator

#Left 4 dead 2 g2a Activator

Signaling by G2A is poorly understood, and varies widely depending on its activator and the responding cell type and inflammatory context ( 8). lymphocytes, monocytes, and granulocytes ( ( 8)). The g-protein coupled receptor, Gpr132 (G2A) is expressed on most leukocytes, e.g. The acute phase is characterized by the production of pro-inflammatory cytokines, including IFNγ, similar to that observed in human IBD ( 4– 7). The dextran sodium sulfate (DSS) model of murine colitis results from direct epithelial injury followed by recruitment of inflammatory cells and their inappropriate response to the microflora of the gut ( 3). IFNγ, present in IBD, has been shown to have a pro-inflammatory role in a number of autoimmune and inflammatory diseases ( 1, 2). Studies to date indicate that cytokines and chemokines that are produced locally at sites of inflammation play an important role in onset and progression of IBD. Since the epithelium functions as the critical interface between the intestinal lumen and the sub-epithelial mucosa, it is thereby anatomically positioned as a central coordinator of mucosal inflammatory response. Epithelial cells are crucial in the maintenance of colonic tissue homeostasis, as IBD is characterized by a breakdown of the intestinal epithelial barrier leading to increased exposure of the mucosal immune system to antigenic luminal material. The most recent evidence suggests IBD results from an inappropriately directed inflammatory response to the intestinal microbiota in a genetically susceptible host. The inflammatory bowel diseases (IBD), including both ulcerative colitis (UC) and Crohn’s disease, are debilitating mucosal disorders of unknown etiology ( 1). Taken together, the data suggest that G2A signaling serves to dampen intestinal inflammation via the production of IFNγ, which in turn, enhances monocyte maturation to a less inflammatory program and ultimately reduces eosinophil-induced injury of colonic tissues. Further, IFNγ reduced the numbers of TNFα + monocyte and enhanced their maturation from Ly6C hiMHCII − to Ly6C intMHCII +. Administration of IFNγ to G2A −/− mice during dextran sodium sulfate exposure abolished the excess colitic inflammation, and reduced colonic IL-5 and eosinophil numbers to levels seen in WT mice. Fewer CD4 + lymphocytes were recruited to inflamed G2A −/− colons and fewer colonic lymphocytes produced IFNγ upon ex vivo stimulation. G2A −/− mice also had less IFNγ in inflamed colon tissues than wild type mice.

Both monocytes and eosinophils were pathogenic as their depletion abolished the excess inflammation in G2A −/− mice. Investigation of inflammatory cells recruited to inflamed G2A −/− colons showed significantly more TNFα + and Ly6C hiMHCII − “pro-inflammatory” monocytes and eosinophils than in wild type colons. Surprisingly, G2A −/− mice exhibited significantly worsened colitis compared to wild type mice as demonstrated by disease activity, colon shortening, histology, and elevated IL-6 and IL-5 in colon tissues. This prompted the hypothesis that genetic deletion of G2A would limit intestinal inflammation in a mouse model of colitis induced by dextran sodium sulfate. Pro-inflammatory consequences have been described for lysophosphatidylcholine, a lipid product of cellular injury, signaling via the g-protein coupled receptor G2A on myeloid and lymphoid inflammatory cells.