title: Developmental Role of Macrophage Cannabinoid-1 Receptor Signaling in Type 2 Diabetes.
abstract: 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 increasedIrf5expression, whereas knockdown ofIrf5blunted CB1R-induced secretion of inflammatory cytokines without affecting CCL2 expression, which was p38MAPKα dependent. Macrophage-specific in vivo knockdown ofIrf5protected 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.
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD tony.jourdan@nih.gov george.kunos@nih.gov.
authors.forename: Tony
authors.initials: T
authors.lastname: Jourdan
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Gergő
authors.initials: G
authors.lastname: Szanda
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Resat
authors.initials: R
authors.lastname: Cinar
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: David J
authors.initials: DJ
authors.lastname: Holovac
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Park
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Nicoloro
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Yuefei
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Division of Renal Pathology, Department of Pathology, Johns Hopkins University, Baltimore, MD.|Kidney Diseases Section, National Institute on Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Avi Z
authors.initials: AZ
authors.lastname: Rosenberg
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Czech
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD tony.jourdan@nih.gov george.kunos@nih.gov.
authors.forename: George
authors.initials: G
authors.lastname: Kunos
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics* / Q000378:metabolism; D055786:Gene Knockout Techniques; D006943:Hyperglycemia / Q000235:genetics* / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000378:metabolism; D053583:Interleukin-1beta; D007515:Islets of Langerhans / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; C000594089:IL1B protein, rat; C000613821:IRF5 protein, rat; D050835:Interferon Regulatory Factors; D053583:Interleukin-1beta; D043884:Receptor, Cannabinoid, CB1; D014409:Tumor Necrosis Factor-alpha