Chloride channels and mast cell function: pioneering new frontiers in IBD therapy.

Emerging evidence indicates that chloride channels (ClCs) significantly affect the pathogenesis of inflammatory bowel disease (IBD) through their regulatory roles in mast cell function and epithelial integrity. IBD, encompassing conditions such as Crohn's disease and ulcerative colitis, involves chronic inflammation of the gastrointestinal tract, where channels influence immune responses, fluid balance, and cellular signalling pathways essential for maintaining mucosal homeostasis. This review examines the specific roles of ClC in mast cells, focussing on the regulation of mast cell activation, degranulation, cytokine release, and immune cell recruitment in inflamed tissues. Key channels, including Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and ClC-2, are discussed in detail because of their involvement in maintaining intestinal epithelial barrier function, a critical factor disrupted in IBD. For example, CFTR facilitates chloride ion transport across epithelial cells, which is essential for mucosal hydration and maintenance of the intestinal barrier. Reduced CFTR function can compromise this barrier, permitting microbial antigens to penetrate the underlying tissues and triggering excessive immune responses. ClC-2, another chloride channel expressed in mast cells and epithelial cells, supports tight junction integrity, contributes to barrier function, and reduces intestinal permeability. Dysregulation of these channels is linked to altered mast cell activity and excessive release of pro-inflammatory mediators, exacerbating IBD symptoms, such as diarrhoea, abdominal pain, and tissue damage. Here, we review recent pharmacological strategies targeting ClC, including CFTR potentiators and ClC-2 activators, which show the potential to mitigate inflammatory responses. Additionally, experimental approaches for selective modulation of chloride channels in mast cells have been explored. Although targeting ClC offers promising therapeutic avenues, challenges remain in achieving specificity and minimizing side effects. This review highlights the therapeutic potential of Cl channel modulation in mast cells as a novel approach for IBD treatment, aiming to reduce inflammation and restore intestinal homeostasis in affected patients.