Circulating Interleukin-6 Mediates PM2.5-Induced Ovarian Injury by Suppressing the PPARγ Pathway

Yingying Chen; Jinjin Zhang; Tianyu Zhang; Yaling Wu; Yueyue Xi; Tong Wu; Mo Li; Yan Li; Su Zhou; Mingfu Wu; Shixuan Wang

doi:10.34133/research.0538

Circulating Interleukin-6 Mediates PM_2.5-Induced Ovarian Injury by Suppressing the PPARγ Pathway

Research (Wash D C). 2024 Dec 5:7:0538. doi: 10.34133/research.0538. eCollection 2024.

Authors

Yingying Chen^{1

2}, Jinjin Zhang^{1

3}, Tianyu Zhang^{1

3}, Yaling Wu^{1

3}, Yueyue Xi^{1

3}, Tong Wu^{1

3}, Mo Li^{1

3}, Yan Li^{1

3}, Su Zhou^{1

3}, Mingfu Wu^{1

3}, Shixuan Wang^{1

3}

Affiliations

¹ Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
² Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
³ Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Abstract

Exposure to airborne fine particulate matter (PM_2.5) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM_2.5 markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM_2.5-exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM_2.5 exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca-interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca-interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM_2.5-induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM_2.5-induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.