title: Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization.
abstract: Human T2D is characterized by a low-grade systemic inflammation, loss of β-cells, and diminished insulin production. Local islet immunity is still poorly understood, and hence, we evaluated macrophage subpopulations in pancreatic islets in the well-established murine model of T2D, the db/db mouse. Already at 8 weeks of disease, on average, 12 macrophages were observed in the diabetic islets, whereas only two were recorded in the nondiabetic littermates. On a detailed level, the islet resident macrophages increased fourfold compared with nondiabetic littermates, whereas a pronounced recruitment (eightfold) of a novel subset of macrophages (CD68+F4/80-) was observed. The majority of the CD68+F4/80+ but only 40% of the CD68+F4/80- islet macrophages expressed CD11b. Both islet-derived macrophage subsets expressed moderate MHC-II, high galectin-3, and low CD80/CD86 levels, suggesting the cells to be macrophages rather than DCs. On a functional level, the vast majority of the macrophages in the diabetic islets was of the proinflammatory, M1-like phenotype. The systemic immunity in diabetic animals was characterized by a low-grade inflammation with elevated cytokine levels and increase of splenic cytokine, producing CD68+F4/80- macrophages. In late-stage diabetes, the cytokine signature changed toward a TGF-β-dominated profile, coinciding with a significant increase of galectin-3-positive macrophages in the spleen. In summary, our results show that proinflammatory M1-like galectin-3+ CD80/CD86(low) macrophages invade diabetic islets. Moreover, the innate immunity matures in a diabetes-dependent manner from an initial proinflammatory toward a profibrotic phenotype, supporting the concept that T2D is an inflammatory disease.
authors.affiliation: 1.Novo Nordisk A/S, Novo Nordisk Park, DK-2760 M°aløv, Denmark. axrd@novonordisk.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Cucak
authors.forename: Lars Groth
authors.initials: LG
authors.lastname: Grunnet
authors.forename: Alexander
authors.initials: A
authors.lastname: Rosendahl
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000943:Antigens, Differentiation / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001786:Blood Glucose; D016207:Cytokines / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D016130:Immunophenotyping; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000096:biosynthesis / Q000172:deficiency; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D010641:Phenotype; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D016207:Cytokines; D018836:Inflammation Mediators; D007328:Insulin; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C036763:monocyte-macrophage differentiation antigen
keywords: cytokines; inflammation; insulin