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We sought to determine the contribution of resident islet macrophages to IAPP-induced inflammation and \u03b2-cell dysfunction. In cultured islets, macrophages (F4\/80+CD11b+CD11c+ cells) were required for IAPP-induced mRNA expression of the proinflammatory cytokines IL-1\u03b2, tumor necrosis factor-\u03b1, and IL-6 and the anti-inflammatory cytokines IL-10 and IL-1 receptor antagonist. Moreover, IAPP-induced IL-1\u03b2 synthesis and caspase-1 activation were detected in macrophages but not other islet cell types. Transgenic mice with \u03b2-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\u2013mediated 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 \u03b2-cells from IAPP-induced islet dysfunction.<\/jats:p>","DOI":"10.2337\/db13-0863","type":"journal-article","created":{"date-parts":[[2013,11,12]],"date-time":"2013-11-12T23:19:10Z","timestamp":1384298350000},"page":"1698-1711","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":219,"title":["Resident Macrophages Mediate Islet Amyloid Polypeptide\u2013Induced Islet IL-1\u03b2 Production and \u03b2-Cell Dysfunction"],"prefix":"10.2337","volume":"63","author":[{"given":"Clara Y.","family":"Westwell-Roper","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan A.","family":"Ehses","sequence":"additional","affiliation":[{"name":"Department of Surgery, Child & Family Research Institute, University of British Columbia, Vancouver, BC, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. 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