IL-34 is expressed in the pancreas and regulates local inflammation.

Interleukin-34, a ligand of CD115, controls Langerhans cells and microglia homeostasis and acts as regulatory cytokine. Here, we describe an unexpected role for IL-34 in metabolic homeostasis. We show that IL-34 is constitutively expressed by human β-cell and mouse islets of Langerhans. β-cell specific genetic invalidation of Il34 in mice (IL-34ΔPdx) impaired glucose tolerance associated with increased inflammation in islets of Langerhans during aging. This phenotype was exacerbated when IL-34ΔPdx mice were subjected to a high-fat diet, suggesting a role for IL-34 in controlling local inflammation. Accordingly, in the presence of pro-inflammatory cytokines, ex vivo murine islets of Langerhans exhibited a decreased insulin synthesis, which was restored in the presence of IL-34. Finally, we observed that the levels of Il-34 mRNA were elevated in islets of Langerhans from type 2 diabetic donors. Collectively, these results identify IL-34 as a major regulator of pancreas inflammation.