Testicular immunomodulation and orchitis: Roles of Tyro3/ Axl/Mer receptor tyrosine kinases and pattern recognition receptors

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Human infertility affects approximately 15% of couples at reproductive age worldwide. Male factors contribute up to 45% of infertility cases. Inflammatory conditions in the male genital system are responsible for about 10% of male infertility in developed countries, and the incidence of immunological infertility can be considerably higher in developing countries where medical cares and environment conditions are poor. In particular, immunological disorders in the testis freguently cause infertility because it is a organ where spermatogenesis carries out. The testis possesses a special immune environment because of its immunoprivileged status and innate immune system. Testicular immune privilege is essential for the protection of male germ cells from detrimental immune responses, whereas the local innate immune system plays a crucial role in the testicular defense against microbial infections. Most of testicular cells are involved in the regulation of testicular immune homeostasis. Disruption of testicular immune homeostasis may result in orchitis, one aetiological factor of male infertility. Multiple mechanisms cooperatively regulate testicular immune homeostasis. Recent studies have revealed important roles of Tyro3/Axl/Mer (TAM) receptor tyrosine kinases and pattern recognition receptors (PRRs) in regulating testicular immune environment. TAM receptors belong to one subfamily of receptor tyrosine kinases. The product of growth arrest-specific gene 6 (Gas6) is common ligand of TAM receptors. TAM and Gas6 are expressed in the testis. TAM triple knockout mice are male sterile and develop autoimmune orchitis. TAM receptors regulate testicular immune homeostasis via three mechanisms: (i) PRR-initiated innate immune responses in Sertoli and Leydig cells are inhibited by TAM/Gas6 signaling, which reduce inflammatory cytokine production in the testis; (ii) TAM receptors promote phagocytosis of apoptotic germ cells by Sertoli cells. The phagocytic clearance of apoptotic germ cells by Sertoli cells can remove germ cell antigens, thereby preventing endogenous immune response; (iii) TAM receptors favor systemic immune tolerance to male germ cells. Experimental autoimmune orchitis (EAO) is a testis-specific autoimmune inflammation in rodent animals after immunization with male germ cell antigens. Axl and Mer double knockout mice are susceptible to EAO induction, suggesting Axl and Mer cooperatively regulate the systemic immune tolerance to male germ cell antigens. Although the testis is an immunoprivileged organ, it can be infected by a broad spectrum of microbial pathogens. However, the testis usually recovers from microbial infections without evident inflammatory response, suggesting that the testis adopts an effective local innate defense system against invading microorganisms. Recognition of microbial pathogens by PRRs initiates innate immune responses, which is the first line of the host defense against invading microbes. Several subfamilies of PRRs are expressed in the testis. In particularly, major testicular cells, including Sertoli, Leydig, and male germ cells, express various PRRs. PRRs can be activated in testicular cells by pathogen molecular patterns, thereby initiating innate immune responses. These observations indicate that testicular cells are equipped with innate immune machinery and may be involved in the testicular defense against microbial infections. This article describes role of TAM receptors and PRRs in regulating immune environment in the testis, and speculates aspects of which need priorizing in future investigation.