biostudies-literatureJourdan TNIDDK NIH HHSNIH994-1007https://www.ebi.ac.uk/biostudies/studies/S-EPMC5360301biostudies-literatureUnknown66(4)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 proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB₁R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB₁R are protected from β-cell loss, hyperglycemia, and nephropathy that are 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, 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, CB₁R activation increased <i>Irf5</i> expression, whereas knockdown of <i>Irf5</i> blunted CB₁R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown of <i>Irf5</i> 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.DiabetesDevelopmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes.PMC5360301R01 DK103047DK-103047Cinar RLiu JRosenberg AZSzanda GPark JKNicoloro SLiu ZCzech MPKunos GJourdan TGodlewski GShen YHolovac DJfalseDevelopmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes.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 proinflammatory signaling in macrophages infiltrating pancreatic islets. Here, we analyzed CB₁R signaling in macrophages and its developmental role in T2D. ZDF rats with global deletion of CB₁R are protected from β-cell loss, hyperglycemia, and nephropathy that are 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, 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, CB₁R activation increased <i>Irf5</i> expression, whereas knockdown of <i>Irf5</i> blunted CB₁R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown of <i>Irf5</i> 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.2017-01-01T00:00:00Z2017 Apr2024-02-15T02:23:37.631Z2019-03-26T23:22:07ZS-EPMC53603012808245810.2337/db16-1199