WFS1 Gene Mutation (c.2389G > A) Induces Immune Disorders by Promoting DC Maturation through Inhibition of TMEM176A.

Mutations in the WFS1 gene, encoding wolframin (WFS1), are known to cause endoplasmic reticulum (ER) stress and lead to Wolfram Syndrome (WS). However, the role of WFS1 in immune inflammation remains unexplored. In this study, we identified that the WFS1 gene mutation (c.2389G > A) not only results in WS associated symptoms but also induces the elevated levels of pro-inflammatory cytokines (i.e. TNF-α, IL-1β, and IL-6), and promotes the maturation of dendritic cell (DC) in WFS1 mutated mice. Silencing the WFS1 gene in DCs also promoted DC maturation and inflammation while also increasing DC apoptosis. Further investigation revealed that WFS1 regulates the expression of X-box binding protein 1 (XBP1), which negatively modulates the expression of TMEM176A, thereby affecting the maturation, inflammatory response, and function of DCs. Additionally, WFS1 influences DC apoptosis under ER stress (ERS) through the ATF4/CHOP pathway. Notably, the WFS1 mutation (c.2389G > A) induces immune cell apoptosis in experimental autoimmune uveitis (EAU). This study is the first to report the immune regulatory mechanism of WFS1 in DCs. The identification of a systemic chronic inflammatory state associated with WFS1 deficiency offers new insights that may facilitate the development of innovative, personalized therapeutic approaches for WS.