Trem2 contributes to the protection against cryptorchidism outcomes via modulating testicular macrophages
Description
Reduced hormone insulin-like 3 (Insl3), exclusively secreted by Leydig cells, has been identified as a recognized mechanism of cryptorchidism. Testicular macrophages in the testicular interstitium likely promote Leydig cell hormone secretion, but their exact role in cryptorchidism remained poorly understood. Here, based on publicly available RNA-sequencing (RNA-seq) data from normal and cryptorchidism testis samples in our previous research, triggering receptor expressed on myeloid cells-2 (Trem2) emerges as the most significant macrophage marker gene associated with human cryptorchidism. In Trem2-/- mouse testes at embryonic day 16.5 (E16.5), there is a noted reduction in Insl3 levels, resulting in approximately 60% of the mice exhibiting cryptorchidism. In our investigation into the underlying cause, we found that Trem2-silenced macrophages impaired the proliferative capacity of Leydig cells. Testicular macrophages acquired a distinctive transcriptional profile in unique cytoplasmic cross-fingering interactions with Leydig cells, primarily mediated by the Trem2-DNAX activation protein 12 (Dap12) receptor complex, which transduces intracellular signals via the spleen tyrosine kinase (Syk) and phosphoinositide 3-kinase (PI3K). Mechanistically, we found a reduction in the level of transforming growth factor-β (TGF-β), accompanied by elevated levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in RAW264.7 cells by ketoconazole (KET) treatment. Additionally, we found a positive correlation between Trem2 and Insl3 expression in a human ex vivo tissue culture model. In summary, our study proposes Trem2 as a novel target for maintaining normal testicular descent by regulating the testicular immune microenvironment. Trial registration: NCT, NCT06560086. Registered 15 August 2024 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000ETTJ&selectaction=Edit&uid=U0007KLC&ts=2&cx=-ii92sy.
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Reduced hormone insulin-like 3 (Insl3), exclusively secreted by Leydig cells, has been identified as a recognized mechanism of cryptorchidism. Testicular macrophages in the testicular interstitium likely promote Leydig cell hormone secretion, but their exact role in cryptorchidism remained poorly understood. Here, based on publicly available RNA-sequencing (RNA-seq) data from normal and cryptorchidism testis samples in our previous research, triggering receptor expressed on myeloid cells-2 (Trem2) emerges as the most significant macrophage marker gene associated with human cryptorchidism. In Trem2-/- mouse testes at embryonic day 16.5 (E16.5), there is a noted reduction in Insl3 levels, resulting in approximately 60% of the mice exhibiting cryptorchidism. In our investigation into the underlying cause, we found that Trem2-silenced macrophages impaired the proliferative capacity of Leydig cells. Testicular macrophages acquired a distinctive transcriptional profile in unique cytoplasmic cross-fingering interactions with Leydig cells, primarily mediated by the Trem2-DNAX activation protein 12 (Dap12) receptor complex, which transduces intracellular signals via the spleen tyrosine kinase (Syk) and phosphoinositide 3-kinase (PI3K). Mechanistically, we found a reduction in the level of transforming growth factor-β (TGF-β), accompanied by elevated levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in RAW264.7 cells by ketoconazole (KET) treatment. Additionally, we found a positive correlation between Trem2 and Insl3 expression in a human ex vivo tissue culture model. In summary, our study proposes Trem2 as a novel target for maintaining normal testicular descent by regulating the testicular immune microenvironment. Trial registration: NCT, NCT06560086. Registered 15 August 2024 - Retrospectively registered, https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000ETTJ&selectaction=Edit&uid=U0007KLC&ts=2&cx=-ii92sy.
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Funding
National Natural Science Foundation of China
82471631
National Natural Science Foundation of China
82171587
Natural Science Foundation of Nantong Municipality
JC2023100