Visual Abstract
We have found that aggregation of the β-cell peptide human islet amyloid polypeptide (hIAPP) causes inflammation and toxicity in islet endothelial cells (IECs), which likely contributes to the islet capillary abnormalities seen in T2D. Based on data from other cell types where hIAPP stimulates the innate immune response, we hypothesized that TLR2/4 signaling is required for the effect of hIAPP on IECs. To test this, we treated MS-1 cells (an immortalized murine IEC cell line) with vehicle control, hIAPP ± the TLR2/4 inhibitor OxPAPc, or, in parallel, the TLR2/TLR4 agonists PAM3CSK4 or LPS for 24h. Cell viability and gene expression were determined. hIAPP resulted in increased levels of inflammatory markers and loss of cell viability (Table). Treatment with the TLR2/4 inhibitor blocked upregulation of Il6 and Vcam1 but not Edn1 expression and did not improve cell viability (Table). Conversely, treatment of IECs with TLR2/4 ligands led to upregulation of Il6 and Vcam1 but not Edn1 expression and did not recapitulate the decrease in cell viability induced by hIAPP (Table). We conclude that TLR2/4 signaling is necessary for the hIAPP-induced proinflammatory response in IECs. In contrast, hIAPP-induced cell death does not require TLR2/4 activation but may contribute to the innate immune response by stimulating release of damage associated molecular patterns and, thereby, inducing TLR signaling.
J. J. Castillo: None. A. Aplin: None. M. F. Hogan: None. A. T. Templin: None. N. Esser: None. R. Akter: None. R. L. Hull: None.
National Institutes of Health (R01DK088082); U.S. Department of Veterans Affairs (BX004063)