Kcnn4 Knockout Induces Salivary Gland Fibrosis, Immune Cell Infiltration, and B-Cell Dysfunction in Mice

Kcnn4 (KCa3.1) is a calcium-activated potassium channel involved in cell volume regulation and immune cell function, but its role in salivary gland homeostasis remains poorly understood. In this study, we generated constitutive Kcnn4 knockout (Kcnn4^-/-) mice to investigate the impact of Kcnn4 loss on salivary glands and systemic inflammation. Histological examination revealed that Kcnn4^-/- mice had enlarged salivary glands with increased collagen deposition (fibrosis) but no major disorganization on H&E staining. mRNA-seq identified 473 differentially expressed genes (DEGs), with significant enrichment of T- and B-cell-related pathways. Immunofluorescence showed markedly increased infiltration of CD4⁺, CD8⁺ T cells and CD19⁺ B cells into the salivary glands of knockout mice, yet local IgG levels were significantly decreased, which was confirmed by western blotting. Olink proteomic analysis of serum from Kcnn4^-/- mice revealed that among 43 targeted inflammatory proteins, 16 were significantly changed; 15 of these (including Il-6, Tnf, Cxcl1) were decreased, while only Csf1 was increased, indicating a broad systemic anti-inflammatory shift. Collectively, these findings demonstrate that Kcnn4 deficiency induces salivary gland fibrosis, promotes T/B cell infiltration, impairs local antibody production, and suppresses systemic inflammatory mediators, uncovering an unexpected role of Kcnn4 in integrating tissue remodeling and immune function in the salivary gland.