Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-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)-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.
Department of Pathology and Laboratory Medicine, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada.
Clara Y
CY
Westwell-Roper
Jan A
JA
Ehses
C Bruce
CB
Verchere
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053583:Interleukin-1beta / Q000096:biosynthesis*; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000378:metabolism / Q000473:pathology
D016207:Cytokines; D053583:Interleukin-1beta; D058228:Islet Amyloid Polypeptide