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CaMK4‐dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis
Author(s) -
Zhan ChangSheng,
Chen Jia,
Chen Jing,
Zhang LiGang,
Liu Yi,
Du HeXi,
Wang Hui,
Zheng MeiJuan,
Yu ZiQiang,
Chen XianGuo,
Zhang Li,
Liang ChaoZhao
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201902910rrr
Subject(s) - autoimmunity , prostatitis , protein kinase b , pi3k/akt/mtor pathway , rar related orphan receptor gamma , phosphorylation , cancer research , kinase , intracellular , interleukin 17 , immunology , microbiology and biotechnology , medicine , chemistry , inflammation , biology , signal transduction , prostate , immune system , foxp3 , cancer
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 Thr 196 p‐CaMK4 was increased in the Th17 cells of the EAP group, which were activated by intracellular cytosolic Ca 2+ . 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 Ca 2+ 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 Ca 2+ ‐CaMK4‐Akt/mTOR‐IL‐17A axis inhibition may serve as a promising therapeutic strategy for CP/CPPS.