“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 (CB1R)-induced pro-inflammatory signaling in macrophages infiltrating pancreatic islets.
Here, we analyzed CB1R signaling in macrophages and its developmental role in T2Dα. ZDF rats with global deletion of CB1R are protected from β-cell loss, hyperglycemia and nephropathy present in ZDF littermates.
Adoptive transfer of CB1R-/- bone marrow to ZDF rats also prevents β-cell loss and hyperglycemia, but not nephropathy. ZDF islets contain elevated levels of CB1R, IL-1β, TNF-α, the chemokine CCL2 and interferon regulatory factor-5 (IRF5), a marker of M1 inflammatory macrophage polarization.
In primary cultured rodent and human macrophages, CB1R activation increased Irf5 expression, whereas knockdown of Irf5 blunted CB1R-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 CB1R signaling in macrophages and a potential therapeutic target.”