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

Abstract

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.

• Authors: Jing Chen, Jialin Meng, Xiaoling Li, Xiao Li, Yi Liu, Chen Jin, Li Zhang, Zongyao Hao, Xianguo Chen, Meng Zhang, Chaozhao Liang
• Journal: Frontiers in immunology (Front Immunol) Vol. 13 Pg. 875412 ( 2022) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 35693826 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Chen, Meng, Li, Li, Liu, Jin, Zhang, Hao, Chen, Zhang and Liang.

Chemical References

• Annexin A1
• CD44 protein, human
• Hyaluronan Receptors
• Hyaluronic Acid
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Annexin A1 (genetics, metabolism)
• Chronic Pain
• Humans
• Hyaluronan Receptors (genetics, metabolism)
• Hyaluronic Acid
• Inflammation
• Male
• Pelvic Pain (metabolism, pathology)
• Prostatitis (drug therapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Th1 Cells (metabolism)