Curcumin Induces Macrophages Polarization to Alleviate Ulcerative Colitis by Regulating Macrophage Nuclear Morphology via Affecting the Interaction Between Enteric Glial Cells Glial‐Derived Neurotrophic Factor and Casein Kinase 2

Macrophages exhibit dynamic functional phenotype shifts under diverse influences, releasing either anti-inflammatory or pro-inflammatory cytokines and playing a pivotal role in ulcerative colitis (UC) pathogenesis. In recent years, the role of enteric glial cells (EGCs) in maintaining intestinal homeostasis has been increasingly recognized. In this study, we investigated whether the alleviation of UC by curcumin is associated with the regulation of EGCs-macrophage interactions, thereby affecting macrophage polarization and its specific mechanisms. Through animal experiments and flow cytometry, we evaluated the efficacy of curcumin in alleviating UC and its impact on macrophages. Furthermore, GDNF intervention confirmed its pivotal role in curcumin's ability to alleviate UC. Finally, molecular docking, cell experiments, laser confocal microscopy, and transmission electron microscopy were employed to elucidate the molecular mechanism. It was found that curcumin can alleviate UC by promoting macrophages' polarization into anti-inflammatory subtypes, increasing the level of glial cell neurotrophic factor (GDNF) in UC mice, and GDNF treatment can alleviate DSS-induced colon injury. Importantly, we demonstrated that GDNF regulates macrophages' polarization by interacting with CK2 to affect the morphological characteristics of macrophage nucleus. The results of this study further enrich the existing pathways for curcumin to alleviate UC and provide new ideas for the prevention and treatment of UC.