Frontiers in Immunology (May 2022)

HA/CD44 Regulates the T Helper 1 Cells Differentiation by Activating Annexin A1/Akt/mTOR Signaling to Drive the Pathogenesis of EAP

  • Jing Chen,
  • Jing Chen,
  • Jing Chen,
  • Jialin Meng,
  • Jialin Meng,
  • Jialin Meng,
  • Xiaoling Li,
  • Xiaoling Li,
  • Xiaoling Li,
  • Xiao Li,
  • Xiao Li,
  • Xiao Li,
  • Yi Liu,
  • Yi Liu,
  • Yi Liu,
  • Chen Jin,
  • Chen Jin,
  • Chen Jin,
  • Li Zhang,
  • Li Zhang,
  • Li Zhang,
  • Zongyao Hao,
  • Zongyao Hao,
  • Zongyao Hao,
  • Xianguo Chen,
  • Xianguo Chen,
  • Xianguo Chen,
  • Meng Zhang,
  • Meng Zhang,
  • Meng Zhang,
  • Chaozhao Liang,
  • Chaozhao Liang,
  • Chaozhao Liang

DOI
https://doi.org/10.3389/fimmu.2022.875412
Journal volume & issue
Vol. 13

Abstract

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CD44 partcipates in multiple inflammatory reactions. Here, we aimed to investigate the role of CD44 and the ligand, hyaluronan (HA), on chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) pathogenesis. We found that CD44 was universally expressed in CD4+ lymphocytes in the peripheral blood of CP/CPPS patients. After silencing CD44 expression or delivering 4-methylumbelliferone (4-MU), the pain severity and prostatic inflammation were significantly relieved. In vitro assay found that HA/CD44 was able to regulate T helper 1 (Th1) cells differentiation, the deficiency of which diminished experimental autoimmune prostatitis (EAP) susceptibility. Bioinformatic analysis suggested that after HA or 4-MU treatment, mTOR signaling was significantly altered, and these results were confirmed by subsequent Western blotting assay. Besides, mass spectrometry and co-immunoprecipitation assays found that CD44 was able to interact with Annexin A1 (ANX A1), and this kind of interaction stabilized ANX A1 protein and maintained the activation of Akt/mTOR pathway. Meanwhile, HA-treatment-enhanced prostatic inflammation, Th1 cell differentiation, and Akt/mTOR pathway activation were reversed after silencing the expression of ANX A1 using shANX A1-lentivirus. The present study systematically investigates the functional role of HA/CD44 in CP/CPPS and identifies novel mechanisms for HA/CD44 promoting Th1 cell differentiation. Targeting the HA/CD44/ANX A1/Akt/mTOR signaling represents novel potential therapeutic strategies for patients with CP/CPPS.

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