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

Cryptorchidism, affecting 1%-9% of male neonates, represents one of the most prevalent congenital genitourinary anomalies. Genetic studies have highlighted Leydig cell-derived insulin-like 3 (Insl3) as pivotal in cryptorchidism. However, the pathogenic mechanisms underlying decreased Insl3 remain poorly elucidated. Here, we identify triggering receptor expressed on myeloid cells-2 (Trem2) -centered crosstalk between testicular macrophages and Leydig cells as a critical regulator of testicular descent via regulating Insl3 expression. In boys with cryptorchidism, Trem2 in the testes was markedly downregulated. Genetic ablation of Trem2 in mice exhibited the cryptorchidism phenotype, concomitant with impaired proliferation of Leydig cells and reduced Insl3. Additionally, a positive correlation was observed between Trem2 expression and Insl3 levels in in vitro human testicular cultures. Mechanistically, Trem2 deficiency caused an increased tumor necrosis factor-α (TNF-α) expression in macrophages by inactivation of the Dap12-Syk-PI3K signaling pathway, thereby impairing the proliferation of Leydig cells and the subsequent production of Insl3. Notably, pharmacological inhibition of aromatase with ketoconazole further attenuated Trem2 expression, exacerbating Insl3 suppression and Leydig cell quiescence. Collectively, these findings unveil Trem2 as a paracrine sentinel for Insl3-dependent testicular descent, thereby mitigating the risk of cryptorchidism.