1. Estrogen promotes Leydig cell engulfment by macrophages in male infertility
- Author
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Xiangdong Li, Wei Lin, Xiaoyan Zhang, Ituro Inoue, Astushi Tajima, Kenneth S. Korach, Daishu Han, Yong Zhang, Han Zheng, Wanpeng Yu, Jihua Wu, Nafis A. Rahman, George Fu Gao, and Hongwen Zhang
- Subjects
Infertility ,Adult ,Male ,medicine.medical_specialty ,endocrine system ,medicine.drug_class ,Estrogen receptor ,Mice, Transgenic ,Biology ,Models, Biological ,Male infertility ,Mice ,Young Adult ,Aromatase ,Phagocytosis ,Internal medicine ,Testis ,medicine ,Animals ,Humans ,Infertility, Male ,Phospholipids ,Azoospermia ,Mice, Knockout ,Leydig cell ,Estradiol ,GAS6 ,Macrophages ,ta1182 ,Estrogen Receptor alpha ,Leydig Cells ,General Medicine ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Mice, Inbred C57BL ,Disease Models, Animal ,medicine.anatomical_structure ,Endocrinology ,Estrogen ,biology.protein ,Intercellular Signaling Peptides and Proteins ,Estrogen receptor alpha ,Biomarkers ,Research Article ,Signal Transduction - Abstract
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.
- Published
- 2014