Fertility loss and birth defect+s of disrupted Trem2-centered macrophage-Leydig cell crosstalk
Description
Cryptorchidism is a common congenital anomaly in male infants, linked to reduced Leydig cell-derived Insl3 levels. Our study found down-regulation of the macrophage marker Trem2 in the testes and up-regulation of serum sTrem2 in boys with cryptorchidism. A positive correlation between Trem2 expression and Insl3 levels was observed in human testicular cultures. Trem2-null mice (Trem2-/-) exhibit smaller testes and compromised fertility; notably, approximately 61.5% of them develop cryptorchidism, presumably due to the reduction in Insl3 levels. Mechanistically, by inactivation of the Dap12-Syk-PI3K signaling pathway, Trem2 deficiency causes an increased TNF-α expression in macrophages, thereby impairing the proliferation of Leydig cells and the subsequent production of Insl3. Treatment of macrophages with the aromatase inhibitor Ketoconazole resulted in a decrease in Trem2 expression, which was associated with reduced Insl3 levels in Leydig cells. Notably, this treatment exacerbated the anti-proliferative effects on Leydig cells observed in Trem2-deficient contexts. In conclusion, we propose that macrophage Trem2 serves as a sentinel for Insl3 expression in Leydig cells, thereby mitigating the risk of cryptorchidism, and sTrem2 is a serum marker for cryptorchidism in the offspring.