Nackiewicz Dominika, Dan Meixia, Speck Madeleine, Chow Samuel Z, Chen Yi-Chun, Pospisilik J Andrew, Verchere C Bruce, Ehses Jan A
Department of Surgery, Faculty of Medicine, University of British Columbia, BC Children's Hospital Research Institute, 950 W 28 Avenue, Vancouver V5Z 4H4, Canada.
Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA.
iScience. 2020 Jan 24;23(1):100775. doi: 10.1016/j.isci.2019.100775. Epub 2019 Dec 14.
Macrophages play a dynamic role in tissue repair following injury. Here we found that following streptozotocin (STZ)-induced beta-cell death, mouse islet macrophages had increased Igf1 expression, decreased proinflammatory cytokine expression, and transcriptome changes consistent with macrophages undergoing efferocytosis and having an enhanced state of metabolism. Macrophages were the major, if not sole, contributors to islet insulin-like growth factor-1 (IGF-1) production. Adoptive transfer experiments showed that macrophages can maintain insulin secretion in vivo following beta-cell death with no effects on islet cell turnover. IGF-1 neutralization during STZ treatment decreased insulin secretion without affecting islet cell apoptosis or proliferation. Interestingly, high-fat diet (HFD) combined with STZ further skewed islet macrophages to a reparative state. Finally, islet macrophages from db/db mice also expressed decreased proinflammatory cytokines and increased Igf1 mRNA. These data have important implications for islet biology and pathology and show that islet macrophages preserve their reparative state following beta-cell death even during HFD feeding and severe hyperglycemia.
巨噬细胞在损伤后的组织修复中发挥着动态作用。在此我们发现，在链脲佐菌素（STZ）诱导β细胞死亡后，小鼠胰岛巨噬细胞的Igf1表达增加，促炎细胞因子表达减少，并且转录组变化与经历胞葬作用且代谢状态增强的巨噬细胞一致。巨噬细胞即使不是胰岛胰岛素样生长因子-1（IGF-1）产生的唯一来源，也是主要来源。过继转移实验表明，巨噬细胞在β细胞死亡后可在体内维持胰岛素分泌，而对胰岛细胞更新无影响。在STZ治疗期间中和IGF-1可降低胰岛素分泌，而不影响胰岛细胞凋亡或增殖。有趣的是，高脂饮食（HFD）与STZ联合使用会使胰岛巨噬细胞进一步偏向修复状态。最后，db/db小鼠的胰岛巨噬细胞也表现出促炎细胞因子表达减少和Igf1 mRNA增加。这些数据对胰岛生物学和病理学具有重要意义，并表明即使在高脂饮食喂养和严重高血糖期间，胰岛巨噬细胞在β细胞死亡后仍保持其修复状态。
