Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-cell dysfunction

Diabetes. 2014 May;63(5):1698-711. doi: 10.2337/db13-0863. Epub 2013 Nov 12.

Abstract

Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin (IL)-1β secretion by bone marrow-derived macrophages. We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and β-cell dysfunction. In cultured islets, macrophages (F4/80(+)CD11b(+)CD11c(+) cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1β, tumor necrosis factor-α, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1β synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with β-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 β-cells from IAPP-induced islet dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytokines / biosynthesis
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / pathology
  • Insulin Resistance / physiology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Interleukin-1beta / biosynthesis*
  • Islet Amyloid Polypeptide / pharmacology*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Macrophages / drug effects
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Transgenic
  • Obesity / metabolism
  • Obesity / pathology

Substances

  • Cytokines
  • Interleukin-1beta
  • Islet Amyloid Polypeptide