Expansion of Islet-Resident Macrophages Leads to Inflammation Affecting β Cell Proliferation and Function in Obesity

Abstract

SUMMARY The nature of obesity-associated islet inflammation and its impact on β cell abnormalities remains poorly defined. Here, we explore immune cell components of islet inflammation and define their roles in regulating β cell function and proliferation. Islet inflammation in obese mice is dominated by macrophages. We identify two islet-resident macrophage populations, characterized by their anatomical distributions, distinct phenotypes, and functional properties. Obesity induces the local expansion of resident intra-islet macrophages, independent of recruitment from circulating monocytes. Functionally, intra-islet macrophages impair β cell function in a cell-cell contact-dependent manner. Increased engulfment of β cell insulin secretory granules by intra-islet macrophages in obese mice may contribute to restricting insulin secretion. In contrast, both intra- and peri-islet macrophage populations from obese mice promote β cell proliferation in a PDGFR signaling-dependent manner. Together, these data define distinct roles and mechanisms for islet macrophages in the regulation of islet β cells.

Islet macrophages drive islet vascular remodeling and compensatory hyperinsulinemia in the early stages of diabetes

“…The percentage of F4/80 + positive cells were higher in the db/db islets compared to lean mice at 8, 12 and 16 weeks of age ( Figure 1A, right panel). The observed increase in macrophage numbers in db/db mice was further corroborated with CD68 + immunofluorescence ( Figure 1B right panel), suggesting that macrophages are present at higher numbers in db/db islets which is similar to a recent study showing increased islet macrophage numbers in genetically obese (ob/ob) mice (3). We further performed a sub-population analysis of freshly isolated and dissociated islet cells using flow cytometry with a panel of earlier-identified macrophage markers (23).…”

“…We also show that the increased islet macrophage numbers were CD11b + , F4/80 hi , MHCIII + , but lacking Ly6C expression. This islet macrophage phenotype is similarly described in both healthy and obese mice (3,23). The relatively low expression of Ly6C on these cells indicate that these cells were either islet resident macrophages with a self-renewal capacity, or Ly6C + inflammatory monocytes that subsequently shed the Ly6C positivity upon infiltrating the pancreatic islet.…”

“…Another possible mechanism for the increased Ly6Cmacrophages, as noted recently in an obesity model is the movement of peri-islet macrophages into the islet microenvironment. However, macrophage recruitment either from islet periphery or from the monocytic pool has been recently discounted through elegant observations using tagged monocytes in an obese T2D model (3).…”

“…Macrophages are the major immune cell type in pancreatic islets at steady state but their presence per islet remain low (3). Islet macrophages have long been reported to increase during prolonged obesity and in T2D but the functional consequences of increased islet macrophage have always been negative.…”

The role of macrophages in obesity-associated islet inflammation and β-cell abnormalities

“…Many studies point to this inflammatory state as an underlying mechanism for the development of insulin resistance in obesity and T2DM. A number of papers have now demonstrated that this chronic tissue inflammatory state also occurs in pancreatic islets [10][11][12] . Islet inflammation has been described in a variety of mouse models of obesity and T2DM as well as in human islets from patients with obesity and/or T2DM 10 .…”