PMID- 34117507 OWN - NLM STAT- MEDLINE DCOM- 20220331 LR - 20220714 IS - 1432-0428 (Electronic) IS - 0012-186X (Linking) VI - 64 IP - 9 DP - 2021 Sep TI - M1 macrophage-derived exosomes impair beta cell insulin secretion via miR-212-5p by targeting SIRT2 and inhibiting Akt/GSK-3beta/beta-catenin pathway in mice. PG - 2037-2051 LID - 10.1007/s00125-021-05489-1 [doi] AB - AIMS/HYPOTHESIS: Macrophage levels are elevated in pancreatic islets, and the resulting inflammatory response is a major contributor to beta cell failure during obesity and type 2 diabetes mellitus. Previous studies by us and others have reported that exosomes released by macrophages play important roles in mediating cell-to-cell communication, and represent a class of inflammatory factors involved in the inflammatory process associated with type 2 diabetes mellitus. However, to date, no reports have demonstrated the effect of macrophage-derived exosomes on beta cells, and little is known regarding their underlying mechanisms in beta cell injury. Thus, we aimed to study the impact of macrophage-derived exosomes on islet beta cell injury in vitro and in vivo. METHODS: The phenotypic profiles of islet-resident macrophages were analysed in C57BL/6J mice fed a high-fat diet (HFD). Exosomes were collected from the medium of cultured bone marrow-derived macrophages (BMDMs) and from isolated islet-resident macrophages of HFD-fed mice (HFD-Exos). The role of exosomes secreted by inflammatory M1 phenotype BMDMs (M1-Exos) and HFD-Exos on beta cell function was assessed. An miRNA microarray and quantitative real-time PCR (qPCR) were conducted to test the level of M1-Exos-derived miR-212-5p in beta cells. Then, miR-212-5p was overexpressed or inhibited in M1-Exos or beta cells to determine its molecular and functional impact. RESULTS: M1-polarised macrophages were enriched in the islets of obese mice. M1 macrophages and islet-resident macrophages of HFD-fed mice impaired beta cell insulin secretion in an exosome-dependent manner. miR-212-5p was notably upregulated in M1-Exos and HFD-Exos. Enhancing the expression of miR-212-5p impaired beta cell insulin secretion. Blocking miR-212-5p elicited a significant improvement in M1-Exos-mediated beta cell insulin secretion during injury. Mechanistically, M1-Exos mediated an intercellular transfer of the miR-212-5p, targeting the sirtuin 2 gene and regulating the Akt/GSK-3beta/beta-catenin pathway in recipient beta cells to restrict insulin secretion. CONCLUSIONS/INTERPRETATION: A novel exosome-modulated mechanism was delineated for macrophage-beta cell crosstalk that drove beta cell dysfunction and should be explored for its therapeutic utility. CI - (c) 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Qian, Bin AU - Qian B AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Yang, Yang AU - Yang Y AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Tang, Ningyuan AU - Tang N AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Wang, Jiahui AU - Wang J AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Sun, Peng AU - Sun P AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Yang, Nan AU - Yang N AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Chen, Fang AU - Chen F AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Wu, Tijun AU - Wu T AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Sun, Tong AU - Sun T AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Li, Yating AU - Li Y AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Chang, Xiaoai AU - Chang X AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Zhu, Yunxia AU - Zhu Y AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. FAU - Zhang, Yaqin AU - Zhang Y AUID- ORCID: 0000-0003-3436-4569 AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. yaqinzhang@njmu.edu.cn. AD - The State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, China. yaqinzhang@njmu.edu.cn. FAU - Han, Xiao AU - Han X AUID- ORCID: 0000-0002-6467-1802 AD - Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China. hanxiao@njmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210611 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 RN - 0 (MicroRNAs) RN - 0 (beta Catenin) RN - EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.5.1.- (Sirt2 protein, mouse) RN - EC 3.5.1.- (Sirtuin 2) SB - IM MH - Animals MH - *Diabetes Mellitus, Type 2/metabolism MH - *Exosomes/metabolism MH - Glycogen Synthase Kinase 3 beta/genetics/metabolism/pharmacology MH - Insulin Secretion MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred C57BL MH - *MicroRNAs/genetics/metabolism MH - Proto-Oncogene Proteins c-akt/metabolism MH - Sirtuin 2/metabolism/pharmacology MH - beta Catenin/genetics/metabolism OTO - NOTNLM OT - Beta cell OT - Exosome OT - Islet inflammation OT - Macrophage OT - miR-212-5p EDAT- 2021/06/13 06:00 MHDA- 2022/04/01 06:00 CRDT- 2021/06/12 06:15 PHST- 2020/12/16 00:00 [received] PHST- 2021/03/25 00:00 [accepted] PHST- 2021/06/13 06:00 [pubmed] PHST- 2022/04/01 06:00 [medline] PHST- 2021/06/12 06:15 [entrez] AID - 10.1007/s00125-021-05489-1 [pii] AID - 10.1007/s00125-021-05489-1 [doi] PST - ppublish SO - Diabetologia. 2021 Sep;64(9):2037-2051. doi: 10.1007/s00125-021-05489-1. Epub 2021 Jun 11.