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 ␤-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 ϩ F4/80 Ϫ ) was observed. The majority of the CD68 ϩ F4/80 ϩ but only 40% of the CD68 ϩ F4/80 Ϫ 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 ϩ F4/80 Ϫ 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 ϩ 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.Abbreviations: db/ ϩ ϭnondiabetic control, db/dbϭhomozygous diabetic, FSCϭforward-scatter, HFDϭhigh fat diet, KCϭkeratinocyte-derived chemokine, SSCϭside-scatter, T1/2Dϭtype 1/2 diabetes Article 0741-5400/14/0095-149

Polarization of Macrophages in Metabolic Diseases

“…"early T2D" (Figure 3) [95]. This coincides with an increased systemic M1-like macrophage population in the spleen fuelling the systemic lowgrade inflammation by enhancing the production of IL-6, TNF-α and IL-1β.…”

“…Egushi et al, elegantly demonstrated that during palmitate challenge, the islet immigrating macrophages to be M1-like CD11b + Ly6C high cells producing significant levels of IL-1β and TNF-α [90]. Within the diabetic islets the vast majority of the resident CD68 + F4/80 + macrophages expressed CD11b, while only 40% of the newly immigrant CD68 + F4/80 -macrophages were CD11b positive [95]. A similar frequency of Ly6C high macrophages were demonstrated in the CD68 + macrophages regardless expression of F4/80.…”

“…This coincides with an increased systemic M1-like macrophage population in the spleen fuelling the systemic lowgrade inflammation by enhancing the production of IL-6, TNF-α and IL-1β. In chronic T2D disease, when the β-cell mass is significantly reduced and the insulin production capacity per remaining β-cell is markedly reduced, the splenic macrophage population undergoes a repolarization toward an M2-like profile associated with high production of TGF-β [95]. On a detailed level, the islet-immigrating macrophage sub-population was a novel CD68 + F4/80 -sub-population not present in healthy non-diabetic islets whereas the islet resident macrophage population was CD68 + F4/80 + [95].…”

“…In chronic T2D disease, when the β-cell mass is significantly reduced and the insulin production capacity per remaining β-cell is markedly reduced, the splenic macrophage population undergoes a repolarization toward an M2-like profile associated with high production of TGF-β [95]. On a detailed level, the islet-immigrating macrophage sub-population was a novel CD68 + F4/80 -sub-population not present in healthy non-diabetic islets whereas the islet resident macrophage population was CD68 + F4/80 + [95]. Egushi et al, elegantly demonstrated that during palmitate challenge, the islet immigrating macrophages to be M1-like CD11b + Ly6C high cells producing significant levels of IL-1β and TNF-α [90].…”

“…Thus, there are common features in obesity and T2D, such as insulin tolerance, but also clear differences, such as β-cell dysfunction, cell death, and hyperglycaemia. The immunological signature in early diabetes is characterized by an early infiltration of M1 pro-inflammatory macrophages secreting pro-inflammatory cytokines such as TNF-α, IL-β and IL-6 [95]. However, chronic T2D show TGF-β produced from the alternatively activated macrophages for tissue remodelling in combination with a systemic low grade inflammation with an M1/M2 macrophage population contributing to further tissue remodelling by either secreting degrading proteolytic enzymes or by stimulating matrix deposit by secreting inhibitors of the proteolytic enzymes [95].…”