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

Coordinated communication among pancreatic islet cells is necessary for maintenance of glucose homeo-stasis. In diabetes, chronic exposure to pro-inflammatory cytokines has been shown to perturb beta cell communication and function. Compelling evidence has implicated extracellular vesicles (EVs) in modulating physiological and pathological responses to beta cell stress. We report that pro-inflammatory beta cell small EVs (cytokine-exposed EVs [cytoEVs]) induce beta 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 beta cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated beta cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. This work implies a significant role of pro-inflammatory beta cell-derived small EVs in modulating beta cell function, global gene expression, and antigen presentation through activation of the CXCL10/CXCR3 axis.

Automated summary

The study demonstrates that pro-inflammatory beta cell-derived small EVs disrupt beta cell function, promote inflammatory responses, and enhance immune cell recruitment in the islets. Furthermore, CXCL10 chemokine enriched in these EVs binds to CXCR3 receptors on beta cells, modulating inflammatory gene expression and leukocyte recruitment.