Figure 1.

SENP1 deletion augments PAT inflammation and islet immunogenicity. PATs from SENP1-aP2KO mice expressed high levels of IL-6, TNF-a and IL-1β. Proinflammatory cytokines have direct effects on islet immunogenicity and islet β-cell survival. We show that the high concentrations of PAT-derived cytokines directly induce expression of CCL5 and other chemokines (such as CCL2, CCL21, CXCL9 and CXCL10) in adjacent pancreatic islets, chemokines responsible for recruitment of immune cells. Second, proinflammatory cytokines have direct effects on various immune cell types, specifically T cells. These immune cells further release more innate inflammatory cytokines, which damage β cells and break tolerance through activation of adaptive responses. This is a Th1 and Th17 effector T-cell subsets expanded and concomitant with reduction of regulatory T-cell subset in the pancreatic lymph nodes of SENP1deficient mice. Third, the inflammatory cytokines have direct cytotoxic effects on islet β cells. proinflammatory cytokines and cytotoxic T cells triggers β-cell turnover, resulting in the release of autoantigens and endogenous ‘danger signals’ capable of promoting pathologic self-antigen presentation, suggesting a strong mechanistic link between adipose secreted proinflammatory cytokines and T1DM.