Estrogen promotes Leydig cell engulfment by macrophages in male infertility.
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.
Wanpeng
W
Yu
Han
H
Zheng
Wei
W
Lin
Astushi
A
Tajima
Yong
Y
Zhang
Xiaoyan
X
Zhang
Hongwen
H
Zhang
Jihua
J
Wu
Daishu
D
Han
Nafis A
NA
Rahman
Kenneth S
KS
Korach
George Fu
GF
Gao
Ituro
I
Inoue
Xiangdong
X
Li
D000328:Adult; D000818:Animals; D001141:Aromatase / Q000235:genetics / Q000378:metabolism; D053713:Azoospermia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000172:deficiency / Q000235:genetics; D006801:Humans; D007248:Infertility, Male / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007985:Leydig Cells / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008954:Models, Biological; D010587:Phagocytosis; D010743:Phospholipids / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013737:Testis / Q000378:metabolism / Q000473:pathology; D055815:Young Adult; D000099255:Growth Arrest-Specific Protein 6
D001141:Aromatase; D015415:Biomarkers; D004958:Estradiol; D047628:Estrogen Receptor alpha; D036341:Intercellular Signaling Peptides and Proteins; D010743:Phospholipids; D011994:Recombinant Proteins; D000099255:Growth Arrest-Specific Protein 6