2. Academic Validation
  3. MIF regulates T helper 17 cell differentiation by activating the p38 MAPK signaling pathway to drive the pathogenesis of EAP

MIF regulates T helper 17 cell differentiation by activating the p38 MAPK signaling pathway to drive the pathogenesis of EAP

  • Int Immunopharmacol. 2025 Jun 26:159:114959. doi: 10.1016/j.intimp.2025.114959.
Fei Zhang 1,  Rui Feng 2,  Tong Meng 1,  Chen Jin 1,  Song Zhang 1,  Yuyang Xu 1,  Jialin Meng 1,  Cheng Yang 1,  Meng Zhang 3,  Chaozhao Liang 4
Affiliations

Affiliations

  • 1 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China.
  • 2 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China; Department of Urology, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
  • 3 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China. Electronic address: zhangmeng@ahmu.edu.cn.
  • 4 Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, PR China; Institute of Urology, Anhui Medical University, Hefei 230022, PR China; Anhui Province Key Laboratory of Urological and Andrological Diseases Research and Medical Transformation, Anhui Medical University, Hefei 230022, PR China. Electronic address: liang_chaozhao@ahmu.edu.cn.
PMID: 40440956 DOI: 10.1016/j.intimp.2025.114959
Abstract

Background: T helper 17 (Th17) cells contribute to chronic nonbacterial prostatitis (CNP); however, the mechanisms underlying their differentiation are incompletely understood. The present study explored the role of the Macrophage migration inhibitory factor (MIF)/CD74/CD44 axis in Th17 cell differentiation via the p38 MAPK pathway in CNP.

Methods: An experimental autoimmune prostatitis (EAP) model was established to simulate CNP and investigate its pathogenesis. The effects of MIF treatment were assessed via hematoxylin-eosin staining, von Frey tests, flow cytometry, immunohistochemistry, and western blotting. The regulatory role of the MIF/CD74/CD44 axis was further explored using the MIF antagonist ISO-1 and anti-CD74 neutralizing antibody.

Results: MIF treatment exacerbated EAP severity, with increased inflammatory responses and mechanical allodynia. Elevated MIF and CD74/CD44 levels were observed in the EAP group, and these were further increased by MIF treatment and reduced by ISO-1 treatment. Flow cytometry analysis revealed an increased number of CD4 + IL-17 A+ and CD4 + RORγt+ cells in the EAP group, and this was further increased by MIF and decreased by ISO-1 treatment. The anti-CD74 neutralizing antibody reduced inflammation, mechanical allodynia, Th17 cell differentiation, and p38 MAPK activation in the EAP mouse model. In vitro, MIF increased Th17 cell numbers and p38 MAPK activation in naïve CD4+ T cells; these effects were suppressed by the anti-CD74 neutralizing antibody or ISO-1. Inhibition of the p38 MAPK pathway reversed MIF-mediated Th17 differentiation.

Conclusions: The results of the present study revealed that the MIF/CD74/CD44 axis played a critical role in Th17 cell differentiation via the p38 MAPK pathway in CNP. Thus, targeting the MIF/CD74/CD44/p38 MAPK pathway may offer a novel therapeutic strategy for treating chronic prostatitis.

Keywords

CD74; Experimental autoimmune prostatitis; Macrophage migration inhibitory factor; Prostatitis; T helper 17 cells; p38 MAPK.

Figures
Products