The roles of TAM receptor tyrosine kinases in the mammalian testis and immunoprivileged sites
Three members of a receptor tyrosine kinase family, including Tyro3, Axl, and Mer, are collectively called as TAM receptors. TAM receptors have two common ligands, namely, growth arrest specific gene 6 (Gas6) and protein S (ProS). The TAM-Gas6/ProS system is essential for phagocytic removal of apoptotic cells, and plays critical roles in regulating immune response. Genetic studies have shown that TAM receptors are essential regulators of the tissue homeostasis in immunoprivileged sites, including the testis, retina and brain. The mechanisms by which the TAM-Gas6/ProS system regulates the tissue homeostasis in immunoprivileged sites are emerging. The roles of the TAM-Gas6/ProS system in regulating the immune privilege were intensively investigated in the mouse testis, and several studies were performed in the eye and brain. This review summarizes our current understanding of TAM signaling in the testis and other immunoprivileged tissues, as well as highlights topics that are worthy of further investigation.
TAM Receptor Tyrosine Kinases, Innate Immunity, Testis, Immune Privilege, Autoimmune Orchitis, Review
Immunoprivileged tissues are body sites with special immune microenvironments wherein the systemic immune responses to allo-and auto-antigens are significantly reduced (1). Remarkable immunoprivileged tissues in mammals include the testis, eye, brain, and pregnant uterus (2). The immunoprivileged status in these tissues is essential to fulfill their indispensable functions for the maintenance of the species. Although the microenvironments in these tissues exhibit different self-preserving functions, the common goal of the immune privilege is to protect the tissues from detrimental immune response.
Both local immunosuppressive milieu and systemic immune tolerance are involved in the regulation of the immune privilege (3). However, mechanisms underlying immune privilege are not the same among individual immunoprivileged sites because of the difference in physical structures and cellular contents of the tissues. The testis consists of various cells constituting two compartments, namely, the seminiferous tubules and the interstitial spaces (Figure 1). Male germ cells are differentiated in the seminiferous epithelium that is built from Sertoli cells intimately embracing the male germ cells. The blood–testis barrier (BTB), which is formed between two adjacent Sertoli cells by several junction types, separates the germ cell antigens in the tubular lumen from the immunological components in the interstitial spaces. Testosterone is synthesized by Leydig cells in the interstitial spaces. The interstitial spaces also contain blood, lymphatic vessels, and various immune cells, which are mainly macrophages, minor T lymphocytes, mast cells, and dendritic cells (DCs). The seminiferous tubules and the interstitial spaces exhibit immunoprivileged properties (4). Several reviews are consulted for the underlying mechanisms of the testicular immune privilege (3,5-7). Increasing evidence shows that Tyro3, Axl, and Mer (TAM) receptor tyrosine kinases, as well as their two ligands growth arrest specific gene 6 (Gas6) and protein S (ProS), cooperatively regulate the immunoprivileged status in the testis, eye, and brain.
TAM receptor belongs to an unique receptor tyrosine kinase family (8). Tyro3, Axl, and Mer share a similar structure containing two immunoglobulin (Ig)-like domains and two fibronectin type β (FN β) repeats in their extracellular regions, followed by a transmembrane domain and an intracellular protein tyrosine kinase domain (Figure 2). Their two ligands Gas6 and ProS are also identified (9,10). Gas6 and ProS contain an N-terminal gamma-carboxylated glutamic acid (GLA) followed by four epidermal growth factor (EGF)-like domains and a C-terminal sex hormone binding globulin (SHBG)-like domain (Figure 2). Two Ig-like domains in the extracellular N-terminal of TAM receptors bind SHBG-like domains of Gas6 or ProS, which activate intracellular tyrosine kinase and initiate cytoplasmic signaling pathway to regulate multiple biological processes, including survival and proliferation of cells, regulation of innate immunity, and phagocytosis of apoptotic cells. The generation of TAM receptors and their ligand knockout mice promoted the understanding of this system (11-13). Increasing evidence states that TAM signaling negatively regulates the innate immune response and plays a critical role in the resolution of inflammation (14,15). Moreover, TAM receptors facilitate phagocytic removal of apoptotic cells, thereby preventing autoimmune diseases (16-20).
The most evident tissue-specific phenotypes in TAM triple knockout (TAM–/–) mice include male sterility caused by impaired spermatogenesis, blindness caused by degeneration of photoreceptors in the retina, and damages in the brain (13), suggesting that TAM receptors help maintain the tissue homeostasis of immunoprivileged sites. Although the roles of TAM receptors in regulating systemic immune homeostasis were recently reviewed, their tissue-specific functions in immunoprivileged sites are yet to be consulted. This article discusses the current understanding about TAM receptors in the testis and other immunoprivileged tissues.
3. TAM receptors in the testis
3.1. TAM and Gas6 expression in the testis and male infertility of TAM–/– mice
Male TAM–/– mice are sterile because of the progressive loss of spermatogenesis, indicating that TAM receptors play essential roles in the maintenance of testicular function (13). To reveal the roles of TAM receptors in the testis, we examined the expression of TAM and Gas6 in the development of a postnatal mouse testis (21). All three TAM receptors are abundantly expressed in Sertoli cells, but Axl and Mer are also expressed in Leydig cells. By contrast, Gas6 is exclusively expressed in Leydig cells. Notably, germ cells do not express TAM receptors and Gas6.
The impaired spermatogenesis in TAM–/– mice evidently appeared about five weeks, after birth, following the onset of sexual maturation and sperm production (22). Although TAM–/– mice are sterile males, they can fulfill the first wave of spermatogenesis and produce minor sperm with multiple morphological malformations. As the mice aged, the germ cells are progressively lost starting from elongated spermatids to round spermatids, spermatocytes, spermatogonia, and eventually depleted from the seminiferous tubules. The defective spermatogenesis cannot be cell autonomous because the germ cells do not express TAM receptors. Testosterone synthesis in Leydig cells is not affected in TAM–/– mice, suggesting that the defective spermatogenesis is attributed to the potential impairment of Sertoli cell functions (22).
3.2. Involvement of TAM and Gas6 in the uptake of apoptotic germ cells by Sertoli cells
Sertoli cells are only somatic cells within the seminiferous tubules which create an essential microenvironment for spermatogenesis. Sertoli cells provide tropic support to germ cells and phagocytically remove apoptotic germ cells and residual bodies (Figure 3, right). The phagocytic removal of apoptotic germ cells and residual bodies by Sertoli cells is necessary for intrinsic homeostasis and normal spermatogenesis (23). We demonstrated that the TAM-Gas6 system is essential for phagocytic removal of apoptotic germ cells by Sertoli cells (24). TAM receptors collaboratively mediate the phagocytosis of apoptotic germ cells by Sertoli cells. Mer is responsible for triggering phagocytic signaling, whereas Axl and Tyro3 contribute to the recognition and tethering of apoptotic germ cells by Sertoli cells (24). About 75% of spermatogenic cells undergo apoptosis under physiological conditions (25). Additionally, the most cytoplasmic portions of elongated spermatids are shed as residual bodies before sperm cells are released into the lumen of the seminiferous tubules (26). The phagocytic removal of apoptotic cells indicates more than mere waste disposal. Moreover, apoptotic germ cells and residual bodies can become energy sources for Sertoli cells to produce ATP (27) (Figure 3). The phagocytic removal of apoptotic cells prevents autoimmune response by eliminating endogenous autoantigens (28). The impaired phagocytic removal of apoptotic cells is associated with systemic autoimmune diseases (29,30). Mature sperms are exclusively produced within the post-pubertal period, a long time after immunocompetence is established during fetal and early neonatal life. Therefore, several immunogenetic autoantigens are produced by developing germ cells (31). TAM-mediated phagocytic removal of apoptotic germ cells by Sertoli cells will contribute to the maintenance of immunoprivileged status in the testis because the defective removal of apoptotic germ cells induces endogenous inflammation in the testis and may lead to autoimmune orthitis (32).
3.3. Induction of endogenous inflammation by damaged germ cells
Toll-like receptors (TLRs) initiate innate immune response and direct antigen-specific adaptive immunity after recognition of conserved microbial molecular patterns. (33,34). TLRs can also recognize endogenous ligands that can be released from damaged cells, thereby inducing autoimmune response (35). Among the most characterized endogenous ligands, high-mobility group box 1 (HMGB1) and several heat shock proteins (HSPs) trigger endogenous inflammation through the activation of TLR2 and TLR4 (36,37). HMGB1 and HSPs are abundantly expressed in male germ cells (38, 39). Testicular HSPs are involved in the development of infectious and autoimmune orchitis (40,41). We demonstrated that damaged male germ cells induce inflammatory cytokine expression in Sertoli cells through TLRs (Figure 3, left) (42). A previous study confirmed the involvement of HMGB1 in the onset of autoimmune orchitis (43). Accordingly, we clarified that TLR2 and TLR4 mediate experimental autoimmune orchitis (EAO) induction in mice. These observations suggested that TLR-initiated immune response to testicular autoantigens is associated with autoimmune orchitis.
3.4. Inhibition of TLR-initiated testicular innate immune response
TAM receptors are pleiotropic inhibitors of TLR-initiated systemic innate immune response (14). The mechanisms by which TAM receptors regulate immune homeostasis were further investigated (44,45), and these studies proved that TAM signaling inhibits inflammation by limiting the intensity and duration of innate immune response. The abundant expression of TAM receptors and Gas6 in the testis suggests that they inhibit immune response in this organ, thereby contributing to the maintenance of the testicular immune privilege. In fact, TAM-Gas6 signaling inhibits TLR-initiated inflammatory response in Sertoli and Leydig cells (46,47). We further found that the testicular immune privilege in TAM–/– mice is progressively disrupted after sexual maturation (48). TAM–/– male mice spontaneously develop autoimmune orchitis, which is characterized by macrophage and lymphocyte infiltrations into the testis, breakdown of BTB, and generation of autoantibodies against germ cell antigens. Moreover, inflammatory cytokines, including TNF-alpha, IL-6 and MCP-1, are upregulated in the TAM–/– testis. The cytokine upregulation is evident in Sertoli cells, suggesting that the innate immune response is induced in Sertoli cells because of deficient TAM receptors (48). This observation corresponds to our previous finding that TAM-Gas6 system inhibits TLR-mediated inflammatory cytokine expression in Sertoli cells (46). Autoimmune orchitis in TAM–/– mice is exclusively developed after the onset of sexual maturation, at which a large number of germ cells underwent apoptosis and numerous residual bodies were formed. Considering that the phagocytic ability of TAM–/– Sertoli cells is impaired and damaged germ cells induce inflammatory response in Sertoli cells through TLR activation (24,42), we speculate that the TAM-Gas6 system is essential in maintaining the immunoprivileged status in the testis through the promotion of phagocytic removal of apoptotic germ cells and residual bodies by Sertoli cells, as well as the inhibition of TLR-initiated innate immune response in the testicular cells (Figure 3).
3.5. Roles of TAM receptors in tolerating germ cell antigens
In addition to local immunosuppression, the systemic immune tolerance to autoantigens also contributes to the immunoprivileged status. TAM receptors regulate the systemic immune tolerance to germ cell autoantigens. Compared with TAM–/– male mice, which are sterile and eventually developing autoimmune orchitis, Axl and Mer double knockout (Axl–/–Mer–/–) male mice demonstrate normal fertility (22,48). However, Axl–/–Mer–/– mice are susceptible to EAO induction, suggesting that Axl and Mer are important regulators of the systemic immune tolerance to male germ cell antigens (49). EAO is a rodent model for investigating the mechanisms underlying the pathogenesis of autoimmune orchitis, which can be induced by immunizing rodent animals with allogeneic testicular antigens (50). Axl–/–Mer–/– mice develop severe EAO after a single immunization with germ cell antigens emulsified with complete Freund’s adjuvant, which is characterized by infiltration of circulating macrophages and T lymphocytes into the testis, damage of the seminiferous epithelium, impaired permeability of BTB, and generation of autoantibodies against germ cell antigens (50). By contrast, a single immunization does not induce EAO in wild-type (WT) mice. However, mild EAO is developed in Axl–/– or Mer–/– mice after the same immunization, whereas Tyro3–/– mice are not susceptible to EAO induction (49). These observations suggest that Axl and Mer, but not Tyro3, cooperatively regulate the systemic immune tolerance to male germ cell antigens, which is in agreement with the observation that Axl and Mer, but not Tyro3, are expressed in antigen-presenting cells, including dendritic cells and macrophages (14). The mechanisms by which Axl and Mer regulate immune response to germ cell autoantigens represent an important topic for future investigation.
3.6. Roles of TLRs in mediating immune response to germ cell antigens
Autoimmune orchitis is an etiological factor of male infertility (51). The mechanisms that mediate systemic autoimmune response to germ cell antigens are largely unknown. Considering that TAM receptors are inhibitors of TLR-initiated innate immune response and TLRs may initiate autoimmune response to endogenous ligands (52), we speculate that TLRs will mediate autoimmune response to male cell antigens. This hypothesis was proven by our recent study showing that TLR2 and TLR4 cooperatively mediate EAO induction in mice (53). WT mice developed severe autoimmune orchitis after three immunizations with autoantigens. TLR2 or TLR4 knockout mice exhibited relatively low susceptibility to EAO induction compared with WT mice. Remarkably, TLR2 and TLR4 double-knockout mice are almost completely protected from EAO induction. Therefore, Axl/Mer receptors and TLR2/4 regulate systemic autoimmune response to germ cell antigens in opposite manners.
4. TAM receptors in the eye
4.1. Mer receptor is essential for vision
When TAM–/– mice were initially generated, they were recognized as blind because of photoreceptor degeneration (13). The role of TAM receptors in maintaining the retinal homeostasis was confirmed by finding that Mer mutation is responsible for the inherited photoreceptor degeneration in a rat model of retinitis pigmentosa (54). Photoreceptor degeneration can also be observed in Mer single-knockout mice, confirming that Mer plays a critical role in regulating retinal function (55). In agreement with these observations, Mer mutation accounts for a subset of inherited retinitis pigmentosa in humans (56,57).
4.2. Role of Mer in regulating phagocytosis of photoreceptor segments
The mechanisms by which Mer regulates the retinal homeostasis were investigated. The photoreceptor degeneration caused by Mer mutation is cell non-autonomous and reflects the impaired function of the retinal pigment epithelium (RPE) cells (58), which form a highly organized epithelium at the back of the eye. These cells phagocytose the distal ends of outer photoreceptor segments, which are critical in maintaining a constant outer segment length and tissue homeostasis because a large number of outer segment membranes are produced daily. Thus, RPE cell dysfunction may result in various retinal diseases (59). RPE cells in Mer–/– mice exhibit a defect in phagocytically removing photoreceptor components, thereby leading to RPE degeneration and blindness as mice aged (58). RPE cells express Mer and Tyro3, and loss of Mer function downregulates Tyro3 expression in RPE cells (58), suggesting that Mer and Tyro3 cooperatively regulate RPE cell function.
4.3. Immune privilege in the eye
The eye is a remarkable immunoprivileged site (60). In fact, substantial knowledge about immune privilege resulted from investigations on the eye (61). However, non-infectious uveitis commonly threatens sight and is presumed to be an autoimmune disease (62,63). Experimental autoimmune uveitis (EAU) can be induced by immunization of susceptible animals with a purified autoantigen, interphotoreceptor retinoid-binding protein (IRBP) (64). Several TLRs mediate EAU induction, suggesting that TLR signaling is involved in the onset of autoimmune uveitis (65). By contrast, TAM receptors inhibit EAU induction. Immunization of TAM–/– mice with a low dose of IRBP induces the onset of EAU (66), but the same immunization does not induce EAU in WT mice. Further research shows that IRBP immunization predominantly induces Th1 effector response in Axl–/–Mer–/– mice (67). The effect will be cell non-autonomous because T cells do not express Axl and Mer. However, DCs and macrophages express Axl and Mer (14). DCs and macrophages of Axl–/–Mer–/– mice drive Th1 cell differentiation by producing high levels of IL-12 and IL-18.
5. TAM receptors in the brain
The brain was thought to be an immunoprivileged tissue because of the blood–brain barrier (BBB) (68). Although all three TAM receptors are expressed in the brain (69), their roles in this tissue are less understood compared with their roles in the testis and the eye; however, TAM signaling in the regulation of immunoprivileged status in the brain was recently revealed. Tyro3-ProS signaling prevents the disruption of BBB by oxygen/glucose deprivation (70). Inflammatory brain damage and BBB disruption are observed in TAM–/– mice, and antibody deposition and autoreactive T cell infiltration occur in the brain (71). A recent study showed that TAM receptors favor brain neurogenesis by inhibiting microglial cell activation (72). Microglial cells of TAM–/– mice produce high levels of pro-inflammatory cytokines, including IL-6, IL-1beta and TNF-alpha, in response to lipopolysaccharide (LPS) challenge. LPS is a TLR4 agonist that triggers inflammatory response through TLR4 signaling. Several TLRs are expressed in microglial cells and can be activated by their respective ligands (73). TAM receptors can inhibit microglial cell activation through the negative regulation of TLR signaling, thereby restricting intensity and duration of inflammatory response in microglial cells to TLR ligands.
6. TAM function beyond the immunoprivileged tissues
The liver demonstrates special immunoregulatory mechanisms. Although the liver is constantly exposed to microbial products derived from enteric microflora under physiological conditions, no obvious inflammation occurs, which represents a behavior termed as “liver tolerance” (74). However, autoimmune hepatitis (AIH) is a global disease in diverse ethnic groups (75). An evidence shows that TAM receptors participate in maintaining the liver tolerance (76). TAM–/– mice develop persistent inflammatory liver damage resembling AIH, which is manifested by the appearance of interface hepatitis, immune cell infiltrations and elevated inflammatory cytokine levels in the liver. TAM receptors, Gas6 and ProS are abundantly expressed in different cell types of the liver. Tyro3 is only expressed in Kupffer cells, Axl is ubiquitously expressed in all liver cells, and Mer is predominantly expressed in Kupffer and sinusoidal cells. By contrast, Gas6 and ProS are exclusively expressed in liver parenchymal cells. The liver of TAM–/– mice produces high levels of pro-inflammatory cytokines. Various TLRs are expressed in the liver, and overactivation of TLRs may break the liver tolerance and result in AIH (77). TAM receptors can inhibit TLR signaling in hepatic cells under physiological conditions, which remain to be clarified.
TAM receptors and their ligands exhibit multiple other functions, including regulation of platelet stabilization, hemostasis and vascular permeability (11,12,78). TAM receptors are also required for normal megakaryocytopoiesis and platelet production, which are involved in hemostasis regulation (79). Moreover, TAM receptors regulate erythropoiesis (80). The roles of TAM receptors in carcinogenesis are emerging (81). Increasing evidence shows that TAM receptors mediate viral entry (82-85). DCs may be susceptible to viral infection through the inhibition of innate antiviral responses by TAM signaling (86). These recent progresses indicate that TAM receptors play broad roles in many biological processes, which are worthy of further investigation.
7. Concluding remarks
The TAM-Gas6/ProS system plays important roles in regulating numerous biological processes. The key functions of the TAM-Gas6/ProS system include the TAM-mediated phagocytic removal of apoptotic cells and the inhibition of innate immune response, given that sustained endogenous inflammation can lead to a broad spectrum of autoimmune diseases, which are the most evident phenotypes in TAM–/– mice. Cross-talk among TAM functions is important to converge their broad roles, which is worthy of future investigation. In addition to systemic immune disorders, the most severe tissue-specific defects appear in the immunoprivileged sites in TAM–/– mice, including the testis, eye, and brain. Therefore, the roles of TAM receptors in regulating the immune privilege merit further investigation. In this context, Tyro3 deserves great attention. Although Tyro3 is not expressed in immune cells, it is abundantly expressed in all immunoprivileged tissues. In particular, evident defective tissue homeostasis was observed in the immunoprivileged tissues of TAM–/– mice, suggesting that Tyro3 functions in these tissues. Further investigation on the functions of TAM receptors in the immunoprivileged tissues will provide novel insights into the mechanisms underlying autoimmune diseases.
This work was supported by the National Natural Science Foundation of China (Grant Nos: 31171445, 31261160491, 31371518 and 81400421) and Major State Basic Research Project of China (No.2015CB94300).
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