| Background and objectives:The testis is a remarkable immune-privileged site that is necessary to protect the germ cells from systemic immune attack, which is critical for normal spermatogenesis. Tyro3, Axl and Mer (TAM) receptor tyrosine kinases triple knockout (TAM-/-) mice are male sterile. However, the mechanism that TAM receptors regulate male fertility remains unclear. In this study, we examine the role of TAM receptors in maintaining testicular immune homeostasis.Materials and methods:TAM-/-mice were used in this study. Testicular structure and spermatogenesis were examined by histology after hematoxylin-eosin staining. The infiltrations of immune cells into the testis were analyzed using flow cytometry and immunohistochemistry. Electron microscopy and biotin tracer assay were used to examine the structure and permeability of blood-testis barrier (BTB). Sertoli cells and germ cells were isolated. Gene expression was examined using qRT-PCR, Western blot, ELISA and immunohistochemistry.Results:A chronic orchitis is developed in adult TAM-/-mice. As mice aging after the onset of sexual maturity, germ cells were progressively degenerated. Coincidently, macrophage infiltration was observed in the testis of TAM-/-mice ages20and30weeks. Moreover, the integrity of BTB was impaired, and the autoantibodies against germ cell antigens were generated as TAM-/-mice aged. The upregulation of major pro-inflammatory cytokines, including TNF-a, IL-6, and monocyte chemotactic protein1, was predominantly observed in Sertoli cells (SCs). In vitro assays showed that SCs lacking TAM receptors secrete relatively high levels of pro-inflammatory cytokines compared with wild-type controls in response to apoptotic germ cells.Conclusions:These results suggest that TAM receptors play an important role in the maintenance of the immune homeostasis in the testis by regulating SC functions. TAM-/-mice developed chronic orchitis, thus impairing male fertility. |
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