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  2. Pro-inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes

Pro-inflammatory β cell small extracellular vesicles induce β cell failure through activation of the CXCL10/CXCR3 axis in diabetes

  • Cell Rep. 2021 Aug 24;36(8):109613. doi: 10.1016/j.celrep.2021.109613.
Naureen Javeed 1 Tracy K Her 2 Matthew R Brown 2 Patrick Vanderboom 3 Kuntol Rakshit 2 Aoife M Egan 3 Adrian Vella 3 Ian Lanza 3 Aleksey V Matveyenko 4
Affiliations

Affiliations

  • 1 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address: javeed.naureen@mayo.edu.
  • 2 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA.
  • 3 Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA.
  • 4 Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA; Division of Endocrinology, Diabetes, and Metabolism, Mayo Clinic, Rochester, MN 55905, USA.
Abstract

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb β cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to β cell stress. We report that pro-inflammatory β cell small EVs (cytokine-exposed EVs [cytoEVs]) induce β cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T cells and macrophages. Proteomic analysis of cytoEVs shows enrichment of the chemokine CXCL10, with surface topological analysis depicting CXCL10 as membrane bound on cytoEVs to facilitate direct binding to CXCR3 receptors on the surface of β cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory β cell-derived small EVs in modulating β cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

Keywords

CXCL10; diabetes; extracellular vesicles; inflammation; intercellular communication; islet; β cell.

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