Testicular spermatogenic cells activate inflammatory signalling pathways linked to the Toll-like receptors (#36)
Spermatogenesis relies on communication between the developing germ cells and supporting Sertoli cells, however the mechanisms by which these cells communicate are poorly understood. Studies suggested that locally produced cytokines, such as interleukin 1α (IL1α), IL6 and activin are regulated by germ cells throughout the cycle of the seminiferous epithelium. In a similar manner, production of these cytokines by Sertoli cells are stimulated by microbial ligands of the Toll-like receptors (TLRs). TLRs 1-6, which signal to cells via adaptor proteins, such as MyD88, during innate immune responses to infection, have been identified in the Sertoli cells. Moreover, spermatogenic disruption occurs in the MyD88-null mouse, suggesting the involvement of TLR/MyD88 signalling in communication between the germ cells and Sertoli cells as well as during innate immune responses.
In order to confirm the concept of germ cell-mediated TLR signalling, intact spermatogenic cells were isolated from adult mice and separated into purified subsets during three stages of their differentiation: round spermatids (RS), pachytene spermatocytes (P), and residual bodies (RB). Results showed that RAW-ELAM macrophage cells, containing an NFkB-luciferase reporter, were significantly stimulated by RS, P and RB. Murine iMAC macrophages secreted tumour necrosis factor α (TNFα) over 24h when treated with RS, P and RB. P were significantly more effective than either RS or RB. In a series of iMAC cell lines lacking specific TLR-signalling components germ cells did not stimulate TNFα production when TLR2 or TLR4 were absent, but were effective in cells lacking TLR3 or its unique adaptor protein, TRIF. Taken together, these data indicated that germ cells can activate TLR2/4 in cells expressing these receptors.
These studies provide evidence that germ cells activate specific TLR signalling networks in the testes, and provide novel insights into the complex regulation of spermatogenesis, testicular dysfunction and disease.