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

  1. C. Bruce Verchere1,2
  1. 1Department of Pathology & Laboratory Medicine
  2. 2Department of Surgery Child & Family Research Institute, University of British Columbia
  1. Corresponding Author: C. Bruce Verchere, E-mail: bverchere{at}cfri.ubc.ca

Abstract

Islet amyloid polypeptide (IAPP) aggregates to form amyloid fibrils in patients with type 2 diabetes and acts as a potent stimulus for interleukin-1β (IL-1β) secretion in 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 pro-inflammatory cytokines IL-1β, tumor necrosis factor-α, and interleukin-6, as well as the anti-inflammatory cytokines interleukin-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 beta cell human IAPP expression had impaired glucose tolerance, elevated islet Il1b mRNA, and decreased Il10 and I1rn expression following high fat feeding. Islet macrophages were the major source of these transcripts and expressed increased cell-surface Ly6C and CD11c in human IAPP transgenic mice. Clodronate liposome-mediated depletion of islet macrophages improved glucose intolerance and blocked pro-inflammatory gene expression in human IAPP-expressing mice, despite increasing the amount of islet amyloid. These data provide the first evidence that IAPP aggregates skew resident islet macrophages toward a pro-inflammatory phenotype and suggest a mechanism by which anti-inflammatory therapies may protect beta cells from IAPP-induced islet dysfunction.

  • Received May 31, 2013.
  • Accepted November 6, 2013.

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