Resident Macrophages Mediate Islet Amyloid PolypeptideInduced Islet IL-1b Production and b-Cell Dysfunction

Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1 secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and -cell dysfunction. In cultured islets, macrophages (F4/80(+)CD11b(+)CD11c(+) cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1, tumor necrosis factor-, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1 synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with -cell human IAPP (hIAPP) expression had impaired glucose tolerance, elevated islet Il1b mRNA, and decreased Il10 and Il1rn expression following high-fat feeding. Islet macrophages were the major source of these transcripts and expressed increased cell surface Ly6C and CD11c in hIAPP transgenic mice. Clodronate liposome-mediated depletion of islet macrophages improved glucose tolerance and blocked proinflammatory gene expression in hIAPP-expressing mice, despite increasing the amount of islet amyloid. These data provide the first evidence that IAPP aggregates skew resident islet macrophages toward a proinflammatory phenotype and suggest a mechanism by which anti-inflammatory therapies may protect -cells from IAPP-induced islet dysfunction.