| First Author | Westwell-Roper CY | Year | 2014 |
| Journal | Diabetes | Volume | 63 |
| Issue | 5 | Pages | 1698-711 |
| PubMed ID | 24222351 | Mgi Jnum | J:229066 |
| Mgi Id | MGI:5750290 | Doi | 10.2337/db13-0863 |
| Citation | Westwell-Roper CY, et al. (2014) Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1beta production and beta-cell dysfunction. Diabetes 63(5):1698-711 |
| abstractText | Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1beta secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and beta-cell dysfunction. In cultured islets, macrophages (F4/80(+)CD11b(+)CD11c(+) cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1beta, tumor necrosis factor-alpha, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1beta synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with beta-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 beta-cells from IAPP-induced islet dysfunction. |
