Figure 7.

The vicious cycle of inflammation and ER stress accelerates the progression of diabetes in Wolfram syndrome. Schematic of the relationship between ER stress and sterile inflammation in Wolfram syndrome (WS). Diabetes in WS is caused by terminal ER stress-induced pancreatic β-cell apoptosis. Hyperglycemic conditions of WFS1-deficient pancreatic β-cells enhance terminal ER stress and induce sterile inflammation. Experimental high-glucose condition induces pro-inflammatory cytokine gene transcription via the PERK pathway and enhances TXNIP-mediated IL-1β processing through the PERK and IRE1α pathways. This high-cytokine condition accelerates ER stress-mediated cell death and upregulates the pro-inflammatory cytokine gene expression in WFS1-deficient pancreatic β-cells. Secreted chemokines or the hypervascularized environment in the WS islets may cause cell-nonautonomous pancreatic β-cell inflammation, including M1-macrophage infiltration.