Role Of Toll-like Receptors In The Damaged Spermatogenic Cell-induced Testicular Inflammatory Responses In Mice

Testicular inflammation, including noninfectious inflammatory responses in the testis, may impair male fertility. Mechanisms underlying the initiation of noninfectious testicular inflammation are poorly understood. In the current study, we demonstrate that damaged spermatogenic cell products (DSCPs) induce expression of various inflammatory mediators, including TNF-α, IL-1β, IL-6, and macrophage chemotactic protein1(MCP-1), in Sertoli cells. Notably, the DSCP-induced inflammatory gene expression was significantly reduced by knockout Toll-like receptor TLR2or TLR4, and abolished by double knockout TLR2and TLR4(TLR2-/-TLR4-/-). MCP-1secreted by Sertoli cells after stimulation with DSCPs promotes macrophage migration. We also provide evidence that busulfan-induced spermatogenic cell damages in vivo upregulate TNF-a and MCP-1expression in Sertoli cells, and facilitate macrophage infiltration into the testis in wild-type mice. These phenomena were not observed in TLR2-/-TLR4-/-mice. Data indicate that DSCPs induce inflammatory gene expression in Sertoli cells via the activation of TLR2and TLR4, which may initiate noninfectious inflammatory responses in the testis. The results provide novel insights into the mechanisms underlying damaged spermatogenic cell-induced testicular inflammation.