The overall goal of the study is to understand the role of β-arrestins (intracellular scaffolding cell signaling proteins) in inflammation and pathogenesis of sepsis and colitis using mouse models. Using polymicrobial sepsis model, we have demonstrated that both β-arrestin (β-arr) 1 and 2 are critical negative regulators of sepsis-induced inflammation. Inspite of major emphasis on the role of β-arrestins in immune cells, we found that the negative regulatory role of β-arr1 in sepsis-induced inflammation is infact, mediated by its function in the non-hematopoietic compartment. Having demonstrated that β-arr1 aggravated colitis in response to chemically induced colitis models, we further examined the role of β-arrestin2 in gut inflammation. Absence of β-arr2 caused greater extent of intestinal inflammation even in the absence of any exogenous stimuli. Further, T cells from peripheral lymphoid organs in β-arr2 knockout mice had dysregulated activation potential. Consequently, in the dextran sodium sulfate (DSS) model of colitis, β-arr2 knockout mice exhibited significantly higher indices of colitis compared to wild type (WT) mice. Additionally, T cells deficient in β-arr2 displayed altered T cell differentiation pattern with higher Th1 and lower regulatory T cell (Treg) polarization potential. As a result, the colitogenic potential of T cells deficient in β-arr2 as assessed in RAG T cell transfer model of colitis was found to be higher. The systemic wasting disease response though was ameliorated in RAG mice reconstituted with T cells lacking β-arr2, suggesting distinct role for β-arr2 at the active site of microbial interaction (gut) and systemic sites where the response is perhaps initiated by different ligands. Nevertheless, these results demonstrate inhibitory role for β-arr2 in T cell activation, providing protection against overt intestinal inflammation. Our studies therefore suggest cell type specific role for β-arrestins in regulating inflammation that is highly context dependent and further work on discerning the involved molecular mechanisms will likely lead to therapeutic strategies to target β-arrestins in inflammation.
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