Islet-resident macrophage-derived miR-155 promotes β cell decompensation via targeting PDX1
Yan Zhang,
Rong Cong,
Tingting Lv,
Kerong Liu,
Xiaoai Chang,
Yating Li,
Xiao Han,
Yunxia Zhu
Affiliations
Yan Zhang
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Rong Cong
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Tingting Lv
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Kerong Liu
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Xiaoai Chang
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Yating Li
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Xiao Han
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China
Yunxia Zhu
Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China; Corresponding author
Summary: Chronic inflammation is critical for the initiation and progression of type 2 diabetes mellitus via causing both insulin resistance and pancreatic β cell dysfunction. miR-155, highly expressed in macrophages, is a master regulator of chronic inflammation. Here we show that blocking a macrophage-derived exosomal miR-155 (MDE-miR-155) mitigates the insulin resistances and glucose intolerances in high-fat-diet (HFD) feeding and type-2 diabetic db/db mice. Lentivirus-based miR-155 sponge decreases the level of miR-155 in the pancreas and improves glucose-stimulated insulin secretion (GSIS) ability of β cells, thus leading to improvements of insulin sensitivities in the liver and adipose tissues. Mechanistically, miR-155 increases its expression in HFD and db/db islets and is released as exosomes by islet-resident macrophages under metabolic stressed conditions. MDE-miR-155 enters β cells and causes defects in GSIS function and insulin biosynthesis via the miR-155-PDX1 axis. Our findings offer a treatment strategy for inflammation-associated diabetes via targeting miR-155.
