2. Academic Validation
  3. Trem2-dependent Insl3 regulation via Dap12-Syk-PI3K pathway: A new pathogenic mechanism in cryptorchidism

Trem2-dependent Insl3 regulation via Dap12-Syk-PI3K pathway: A new pathogenic mechanism in cryptorchidism

  • Genomics. 2025 Sep 30;117(6):111120. doi: 10.1016/j.ygeno.2025.111120.
Songyi Ye 1,  Chenyu Wu 2,  Shuaijing Huang 3,  Haowen Fan 4,  Zhiqing Zhang 2,  Jinling Chen 5,  Wenliang Ge 6
Affiliations

Affiliations

  • 1 Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China; Department of Pathogen Biology, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
  • 2 Department of Pathogen Biology, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
  • 3 Department of Gastroenterology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, Jiangsu, China.
  • 4 Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China.
  • 5 Department of Pathogen Biology, Medical School of Nantong University, Nantong 226001, Jiangsu, China. Electronic address: chenchennt@ntu.edu.cn.
  • 6 Department of Pediatric Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, Jiangsu, China. Electronic address: gewl@ntu.edu.cn.
PMID: 41038403 DOI: 10.1016/j.ygeno.2025.111120
Abstract

Cryptorchidism, affecting 1 %-9 % of male neonates, represents one of the most prevalent congenital genitourinary anomalies. Studies highlighted Leydig cell derived insulin-like 3 (Insl3) as pivotal in the initial phase of testicular descent. However, the pathogenic mechanisms underlying decreased Insl3 remain poorly elucidated. Here, we showed that triggering receptor expressed on myeloid cells-2 (Trem2) acted as a central mediator in macrophage-Leydig cell communication, influencing testicular descent via Insl3 regulation. In boys with cryptorchidism, Trem2 in testes was markedly downregulated. 63.16 % of Trem2-/- mice exhibited cryptorchidism and abnormal sperm motility and morphology, concomitant with decreased Leydig cells and Insl3. In vitro studies using human testicular cultures also revealed that Trem2 expression positively correlated with Insl3 expression. Mechanistically, ketoconazole elevated TNF-α due to suppression of the Trem2-Dap12-Syk-PI3K axis, ultimately disrupting total Leydig cell number and Insl3 expression. Collectively, these findings unveil Trem2 as a paracrine sentinel for Insl3-dependent testicular descent, thereby mitigating cryptorchidism.

Keywords

Cryptorchidism; Insl3; Macrophages; Trem2.

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