Pro-inflammatory Beta Cell Small Extracellular Vesicles Induce Beta Cell Failure Through Activation of the CXCL10/CXCR3 Axis in Diabetes
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ABSTRACT: 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 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 (cytoEV) induce β-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 β-cells. CXCR3 receptor inhibition reduced CXCL10-cytoEV binding and attenuated β-cell dysfunction, inflammatory gene expression, and leukocyte recruitment to islets. Collectively, this work implicates the 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.
INSTRUMENT(S): Orbitrap Fusion Lumos
ORGANISM(S): Mus Musculus (mouse)
TISSUE(S): Cell Culture, Insulin Secreting Cell
DISEASE(S): Type 2 Diabetes Mellitus
SUBMITTER: Naureen Javeed
LAB HEAD: Naureen Javeed
PROVIDER: PXD026998 | Pride | 2021-08-25
REPOSITORIES: Pride
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