IL-4 triggers salivary duct dilatation via SHH signaling and exacerbates Sjögren’s disease

Primary Sjögren's disease (pSjD) is a chronic autoimmune disease. Clinically, sialography and lip gland biopsy in patients with pSjD show characteristic ductal dilations. However, the roles of the immune responses in ductal dilation remain unknown. We show that Th2 cells and their core cytokine IL-4 promote salivary duct dilatation in human and experimental SjD. Specifically, striated duct dilation is accompanied by periductal lymphocyte infiltration, which is correlated with increased IL-4 levels. In vivo, IL-4 neutralization reduced ductal dilation. Mechanistically, IL-4 induces the formation of cyst-like structures in cultured embryonic submandibular glands of mice. At the molecular level, IL-4 activates SHH signaling pathway in striated duct epithelial cells, upregulating SNAI1 and suppressing Cadherin 1 expression. This process disrupts interepithelial adhesion, leading to ductal dilation. Thus, IL-4 drives salivary gland ductal dilation that interferes with salivary gland function in SjD. Our findings should have implications for a potential therapeutic target in clinical pSjD.