Pro-inflammatory Beta Cell Small Extracellular Vesicles Induce Beta Cell Failure Through Activation of the CXCL10/CXCR3 Axis in Diabetes

Coordinated communication among pancreatic islet cells is necessary for the maintenance of glucose homeostasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb ß-cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to ß-cell stress. We report that pro-inflammatory ß-cell small EVs (cytoEV) induce ß-cell dysfunction, promote a pro-inflammatory islet transcriptome, and enhance recruitment of CD8+ T-cells and macrophages. Proteomic analysis of cytoEV revealed an enrichment of the chemokine, CXCL10, with surface topological analysis depicting CXCL10 as membrane-bound on cytoEV to facilitate direct binding to CXCR3 receptors on the surface of ß-cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated ß-cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. Collectively, this work implicates the significant role of pro-inflammatory ß-cell derived small EVs in modulating ß-cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis. Overall design: 4 samples total were analyzed. 2 replicates for control (UT) islets vs. 2 replicates for cytoEV treated islets