Expression of miRNA-29 in Pancreatic β Cells Promotes Inflammation and Diabetes via TRAF3

  • Cell Rep. 2021 Jan 5;34(1):108576. doi: 10.1016/j.celrep.2020.108576.
Yi Sun  1 ,  Yuncai Zhou  1 ,  Ying Shi  1 ,  Yan Zhang  1 ,  Kerong Liu  1 ,  Rui Liang  2 ,  Peng Sun  1 ,  Xiaoai Chang  1 ,  Wei Tang  3 ,  Yujing Zhang  4 ,  Jing Li  4 ,  Shusen Wang  2 ,  Yunxia Zhu  5 ,  Xiao Han  6
Affiliations
  • 1. Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China.
  • 2. Organ Transplant Center, Tianjin First Central Hospital, Nankai University, Tianjin 300192, China.
  • 3. Department of Endocrinology, Geriatric Hospital of Nanjing Medical University, Nanjing, Jiangsu 210024, China.
  • 4. State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, Jiangsu 210046, China.
  • 5. Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China. Electronic address: [email protected].
  • 6. Key Laboratory of Human Functional Genomics of Jiangsu Province, Biochemistry and Molecular Biology, Nanjing medical University, Nanjing, Jiangsu 211166, China. Electronic address: [email protected].
PMID: 33406428 DOI: 10.1016/j.celrep.2020.108576
Abstract

Type 2 diabetes mellitus (T2DM) is recognized as a chronic, low-grade inflammatory disease characterized by Insulin resistance and pancreatic β cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c mice are predisposed to develop glucose intolerance and Insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β cell miR-29 is largely mediated through macrophages because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and macrophages and, hence, inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.

Keywords
TRAF3; chronic inflammation; exosome; glucose metabolism; insulin resistance; metabolic stress; miR-29; monocytes and macrophages; type 2 diabetes mellitus; β cell dysfunction.
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