Toll-Like Receptor-Initiated Testicular Innate Immune Responses in Mouse Leydig Cells

Shang, Tao; Zhang, Xiaoyan; Wang, Tao; Sun, Bing; Deng, Tingting; Han, Daishu

doi:10.1210/en.2011-0031

Cited by 78 publications

(80 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These immune cells are thought to constitute the frontline of the epididymal defense against invading microbes (35). Increasing evidence has shown that PRR-initiated innate antimicrobial responses also occur in testicular tissue-specific cells, including Sertoli cells, Leydig cells, and male germ cells (40)(41)(42)(43). The present study demonstrated that the mouse epididymis-specific major cells (i.e., EECs) abundantly express viral sensors TLR3, RIG-I, and DAI.…”

Section: Discussionsupporting

confidence: 51%

Pattern Recognition Receptor–Initiated Innate Antiviral Responses in Mouse Epididymal Epithelial Cells

Zhu

Zhao

Liu

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Viral infections of the epididymis may impair male fertility and spread sexually transmitted pathogens. The innate antiviral immune responses in the epididymis have yet to be intensively investigated. This study found that mouse epididymal epithelial cells (EECs) constitutively express several viral sensors, including TLR3, retinoic acid–inducible gene I, and DNA-dependent activator of IFN regulatory factors. Other DNA sensors, including p204 and cGMP-AMP synthase, can be induced by transfection of synthetic HSV genomic DNA (HSV60). TLR3 and retinoic acid–inducible gene I in EECs can be activated by their common agonist, polyinosinic-polycytidylic acid [poly(I:C)]. The signaling pathway of DNA sensors can be initiated by HSV60. Both poly(I:C) and HSV60 induced the expression of type 1 IFNs and various antiviral proteins, including IFN-stimulated gene 15, 2′,5′-oligoadenylate synthetase, and myxovirus resistance 1. Poly(I:C), but not HSV60, also dramatically induced the expression of major proinflammatory cytokines, including TNF-α and MCP-1, in EECs. In vivo assay confirmed that the local injection of poly(I:C) or HSV60 induced the innate antiviral responses in EECs. This study provided novel insights into the mechanisms underlying the innate antiviral responses in the mouse epididymis.

show abstract

Section: Discussionsupporting

confidence: 51%

Pattern Recognition Receptor–Initiated Innate Antiviral Responses in Mouse Epididymal Epithelial Cells

Zhu

Zhao

Liu

et al. 2015

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…83 We also demonstrated that TAM signaling inhibits the innate immune responses in SCs and Leydig cells. 84,85 Moreover, the Gas6/ProS-TAM system facilitates phagocytic clearance of apoptotic germ cells by SCs. 86 The removal of apoptotic germ cells by phagocytes facilitates the elimination of the auto-antigens, which may reduce endogenous inflammation.…”

Section: Immune Privilege In the Testismentioning

confidence: 99%

“…In addition to SCs, we also found that TLR3 and TLR4 are expressed and are functional in murine Leydig cells. 85 Interestingly, TLR-initiated innate immune responses in Sertoli and Leydig cells are negatively regulated by Gas6/ProS-TAM signaling, which may play roles in avoiding sustained inflammatory conditions that could impair testicular functions. 84,85 Different stages of germ cells also express TLRs.…”

Section: Tlrs In Testicular Cellsmentioning

confidence: 99%

“…85 Interestingly, TLR-initiated innate immune responses in Sertoli and Leydig cells are negatively regulated by Gas6/ProS-TAM signaling, which may play roles in avoiding sustained inflammatory conditions that could impair testicular functions. 84,85 Different stages of germ cells also express TLRs. 105 We recently demonstrated that TLR3 in spermatogonia and spermatocytes and TLR11 in spermatids initiate innate immune responses.…”

Section: Tlrs In Testicular Cellsmentioning

confidence: 99%

See 1 more Smart Citation

Testicular defense systems: immune privilege and innate immunity

et al. 2014

Self Cite

View full text Add to dashboard Cite

The mammalian testis possesses a special immunological environment because of its properties of remarkable immune privilege and effective local innate immunity. Testicular immune privilege protects immunogenic germ cells from systemic immune attack, and local innate immunity is important in preventing testicular microbial infections. The breakdown of local testicular immune homeostasis may lead to orchitis, an etiological factor of male infertility. The mechanisms underlying testicular immune privilege have been investigated for a long time. Increasing evidence shows that both a local immunosuppressive milieu and systemic immune tolerance are involved in maintaining testicular immune privilege status. The mechanisms underlying testicular innate immunity are emerging based on the investigation of the pattern recognition receptor-mediated innate immune response in testicular cells. This review summarizes our current understanding of testicular defense mechanisms and identifies topics that merit further investigation.

show abstract

“…TYRO3, MER, and AXL are differentially expressed in LCs, Sertoli cells, and testicular macrophages, respectively (47). GAS6 binds to these TAM receptors with markedly different affinities (AXL≥TYRO3>>MER) (2), and GAS6 binds to AXL-Fc, TYRO3-Fc, and MER-Fc at 0.4, 2.7, and 29.0 nM, respectively (48).…”

Section: Figurementioning

confidence: 99%

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Yu¹,

Zheng²,

Lin³

et al. 2014

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Male infertility accounts for almost half of infertility cases worldwide. A subset of infertile men exhibit reduced testosterone and enhanced levels of estradiol (E2), though it is unclear how increased E2 promotes deterioration of male fertility. Here, we utilized a transgenic mouse strain that overexpresses human CYP19, which encodes aromatase (AROM+ mice), and mice with knockout of Esr1, encoding estrogen receptor α (ERαKO mice), to analyze interactions between viable Leydig cells (LCs) and testicular macrophages that may lead to male infertility. In AROM+ males, enhanced E2 promoted LC hyperplasia and macrophage activation via ERα signaling. E2 stimulated LCs to produce growth arrest-specific 6 (GAS6), which mediates phagocytosis of apoptotic cells by bridging cells with surface exposed phosphatidylserine (PS) to macrophage receptors, including the tyrosine kinases TYRO3, AXL, and MER. Overproduction of E2 increased apoptosis-independent extrusion of PS on LCs, which in turn promoted engulfment by E2/ERα-activated macrophages that was mediated by AXL-GAS6-PS interaction. We further confirmed E2-dependant engulfment of LCs by real-time 3D imaging. Furthermore, evaluation of molecular markers in the testes of patients with nonobstructive azoospermia (NOA) revealed enhanced expression of CYP19, GAS6, and AXL, which suggests that the AROM+ mouse model reflects human infertility. Together, these results suggest that GAS6 has a potential as a clinical biomarker and therapeutic target for male infertility.

show abstract

Toll-Like Receptor-Initiated Testicular Innate Immune Responses in Mouse Leydig Cells

Cited by 78 publications

References 45 publications

Pattern Recognition Receptor–Initiated Innate Antiviral Responses in Mouse Epididymal Epithelial Cells

Pattern Recognition Receptor–Initiated Innate Antiviral Responses in Mouse Epididymal Epithelial Cells

Testicular defense systems: immune privilege and innate immunity

Estrogen promotes Leydig cell engulfment by macrophages in male infertility

Contact Info

Product

Resources

About