Anti-inflammatory effects of WFS1 in pancreatic β-cells

Wolfram syndrome is a rare genetic disorder characterized by juvenile-onset diabetes mellitus, optic nerve atrophy, hearing loss, diabetes insipidus, and progressive neurodegeneration. Pathogenic variants in the WFS1 gene are the main causes of Wolfram syndrome. WFS1 encodes a transmembrane protein localized to the endoplasmic reticulum (ER) and regulates the unfolded protein response (UPR). Loss of function of WFS1 leads to dysregulation of insulin production and secretion, ER calcium depletion, and cytosolic calpains activation, resulting in activation of apoptotic cascades. Although the terminal UPR has been shown to induce inflammation that accelerates β-cell dysfunction and death in diabetes, the contribution of β-cell inflammation to the development of diabetes in Wolfram syndrome has not been fully understood. Here we show that WFS1 -deficiency enhances the gene expression of inflammatory cytokines and chemokines, leading to cytokine-induced ER-stress and cell death in pancreatic β-cells. PERK and IRE1α pathways mediate high glucose-induced inflammation in a β-cell model of Wolfram syndrome. M1-macrophage infiltration and hypervascularization are seen in the pancreatic islets of Wfs1 whole-body knockout mice, demonstrating that WFS1 regulates anti-inflammatory responses in β-cells. Our results demonstrate that inflammation plays an essential role in the progression of β-cell death and diabetes in Wolfram syndrome and reveal that the pathways involved in ER stress-mediated inflammation provide potential therapeutic targets for the treatment of Wolfram syndrome. ### Competing Interest Statement Author F. Urano is a Founder and President of CURE4WOLFRAM, INC and employed by it. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. F. Urano is an inventor of three patents related to the treatment of Wolfram syndrome, SOLUBLE MANF IN PANCREATIC BETA CELL DISORDERS (US 9,891,231) and TREATMENT FOR WOLFRAM SYNDROME AND OTHER ER STRESS DISORDERS (US 10,441,574 and US 10,695,324).