Chronic prostatitis and chronic pelvic pain syndrome (CP/CPPS) is a complicated syndrome characterized by genitourinary pain in the absence of bacterial infection. Th17 cell-driven autoimmunity has been proposed as a cause of CP/CPPS. However, the factors that promote Th17-driven autoimmunity in experimental autoimmune prostatitis (EAP) and the molecular mechanisms are still largely unknown. Here, we showed that Th17 cells were excessively activated, and blockade of IL-17A could effectively ameliorate various symptoms in EAP. Furthermore, we revealed that calcium/calmodulin-dependent kinase Ⅳ (CaMK4), especially Thr196 p-CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca2+ . Pharmacologic and genetic inhibition of CaMK4 decreased the proportion of Th17 cells, and the protein and mRNA level of IL-17A, IL-22, and RORγt. The phosphorylation of CaMK4 was dependent on the increase in intracellular cytosolic Ca2+ concentration in Th17 cells. A mechanistic study demonstrated that inhibition of CaMK4 reduced IL-17A production by decreasing the phosphorylation of Akt-mTOR, which was well accepted to positively regulate Th17 differentiation. Collectively, our results demonstrated that Ca2+ -CaMK4-Akt/mTOR-IL-17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2020 Aug 30 [Epub ahead of print]
Chang-Sheng Zhan, Jia Chen, Jing Chen, Li-Gang Zhang, Yi Liu, He-Xi Du, Hui Wang, Mei-Juan Zheng, Zi-Qiang Yu, Xian-Guo Chen, Li Zhang, Chao-Zhao Liang
Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, China., Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, China., Department of Urology, The First Affiliated Hospital of Anhui University of Chinese Medicine, Hefei, China.