CaMK4-dependent phosphorylation of Akt/mTOR underlies Th17 excessive activation in experimental autoimmune prostatitis

FASEB J. 2020 Oct;34(10):14006-14023. doi: 10.1096/fj.201902910RRR. Epub 2020 Aug 30.

Abstract

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.

Keywords: Akt/mTOR signaling; CaMK4; EAP; Th17.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / immunology*
  • Calcium / metabolism
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / genetics
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4 / metabolism*
  • Interleukin-17 / metabolism
  • Interleukin-22
  • Interleukins / metabolism
  • Lymphocyte Activation*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Receptor Subfamily 1, Group F, Member 3 / metabolism
  • Phosphorylation
  • Prostatitis / immunology*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction*
  • TOR Serine-Threonine Kinases / metabolism
  • Th17 Cells / immunology*

Substances

  • Interleukin-17
  • Interleukins
  • Nuclear Receptor Subfamily 1, Group F, Member 3
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases
  • Calcium-Calmodulin-Dependent Protein Kinase Type 4
  • Camk4 protein, mouse
  • Calcium