Pharmacological inhibition of Na/Caexchanger alleviates colitis via modulation of macrophage activity in multiple species.

Abstract

BACKGROUND: Macrophages play a pivotal role in both the initiation and resolution of intestinal inflammation, positioning them as potential therapeutic target in inflammatory bowel disease. Intracellular ion such as Caare increasingly recognized as key regulators of macrophage function and inflammatory responses. The Na/Caexchanger is a membrane protein predominantly expressed in excitable cells, where it regulates intracellular Naand Caconcentrations. This study aims to elucidate the role of Na/Caexchanger in macrophages and its potential implications for inflammatory bowel disease therapy. METHODS: We investigated macrophage function using Na/Caexchanger inhibitor and evaluated the effects of Na/Caexchanger inhibition in a dextran sodium sulfate-induced mouse model of colitis. RESULTS: Na/Caexchanger-1 expression was elevated inflammatory macrophages and colonic tissues from mice with dextran sodium sulfate-induce colitis. Treatment with the Na/Caexchanger inhibitor SN-6 ameliorated dextran sodium sulfate-induce colitis symptoms and suppressed the release of pro-inflammatory cytokines from murine and canine macrophage. Inhibition of Na/Caexchanger increased Cainflux and promoted phosphorylated of nuclear factor of activated T-cells in mouse macrophages. Furthermore, Na/Caexchanger-1 mRNA expression was upregulated in colonic tissues from both human and canine inflammatory bowel disease patients. CONCLUSIONS: These findings suggest that Na/Caexchanger-1 plays a critical role in inflammatory responses in macrophages. Inhibition of Na/Caexchanger exerts anti-inflammatory effects and attenuates colonic inflammation across multiple species, including humans and dogs, highlighting its potential as a therapeutic target for inflammatory bowel disease.