Accumulation of M1-like macrophages in type 2 diabetic islets is followed by a systemic shift in macrophage polarization

Two distinct subsets of pro-inflammatory M1-like macrophages invade type 2 diabetic islets at a time-point when -cells undergo apoptosis, and blood glucose control is lost. Human T2D is characterized by a low-grade systemic inflammation, loss of -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--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.