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Islet inflammation promotes β-cell loss and type 2 diabetes (T2D), a process replicated in Zucker Diabetic Fatty (ZDF) rats in which β-cell loss has been linked to cannabinoid-1 receptor (CB 1 R)-induced proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB 1 R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB 1 R are protected from β-cell loss, hyperglycemia, and nephropathy that are present in ZDF littermates. Adoptive transfer of CB 1 R -/- bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia but not nephropathy. ZDF islets contain elevated levels of CB 1 R, interleukin-1β, tumor necrosis factor-α, the chemokine CCL2, and interferon regulatory factor-5 (IRF5), a marker of inflammatory macrophage polarization. In primary cultured rodent and human macrophages, CB 1 R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB 1 R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown of Irf5 protected ZDF rats from β-cell loss and hyperglycemia. Thus, IRF5 is a crucial downstream mediator of diabetogenic CB 1 R signaling in macrophages and a potential therapeutic target., (© 2017 by the American Diabetes Association.)