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Contributions of Creatine Kinase to Mucosal Immune Responses in Colitis

Intestinal epithelial cells facilitate nutrient transport as well as protect against invasion of luminal bacteria and microbial products. Disruption of the intestinal epithelial barrier is a hallmark of IBD. The regulation of intestinal epithelial barrier is made possible by junctional complexes including tight junctions and adherens junctions that are supported by the actin cytoskeleton. Maintenance of the actin cytoskeleton is an energy demanding process and intestinal epithelial cells shuttle energy to the locations of the cellular junctions through the creatine‐ATP energy circuit. Within the cell, creatine and its associated enzyme(s) creatine kinase(s) (CK) facilitate the shuttling of high energy phosphates in the form of phosphocreatine between sites of ATP generation. Work in our lab has shown that CK contributes to apical junction assembly in vitro and that supplementation with creatine in murine colitis models is protective. Further studies have shown that mice lacking the brain and mitochondrial isoforms of CK (CK dKO) are significantly more susceptible to DSS‐induced colitis as measured by multiple disease parameters, including disease activity, weight loss, intestinal permeability and by histological assessment. In addition to impaired barrier function, mice lacking CK showed defective inflammatory responses underscored by nearly non‐existent levels of colonic IFNγ. Flow cytometry from splenocytes and MLNs of CK dKO mice showed that T cells produced less IFNγ upon stimulation in vitro, and this finding was confirmed in human PBMC treated with the CK inhibitor cyclocreatine. These results implicate a CK‐dependent regulation of IFNγ in protective innate immune responses during mucosal inflammation, and ongoing studies are focused on elucidating the mechanism of CK activity on T cell signaling.