Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model
<b>Objective<b>:</b></b> Inflammatory arthritis (IA) has been linked to a number of adverse pregnancy outcomes (APOs), but the mechanisms linking IA-related immune dysregulation to compromised reproductive success remain poorly understood. This project will examine how IA aff...
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2025-06-01
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| author | Chenxi Yang Wenjuan Li Xinxin Liu Zijun Ma Jun Chen Quan Gong Zachary Braunstein Xiaoquan Rao Yingying Wei Jixin Zhong |
| author_facet | Chenxi Yang Wenjuan Li Xinxin Liu Zijun Ma Jun Chen Quan Gong Zachary Braunstein Xiaoquan Rao Yingying Wei Jixin Zhong |
| author_sort | Chenxi Yang |
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| description | <b>Objective<b>:</b></b> Inflammatory arthritis (IA) has been linked to a number of adverse pregnancy outcomes (APOs), but the mechanisms linking IA-related immune dysregulation to compromised reproductive success remain poorly understood. This project will examine how IA affects pregnancy outcomes and alters the associated immune microenvironment using SKG (ZAP70<sup>W163C</sup>) mice, a mouse model that suffers from arthritis resembling human IA. <b>Methods:</b> IA was induced in SKG mice on a C57BL/6J background via mannan exposure. Wild-type C57BL/6 mice served as controls. Pregnancy rates, conception time, embryo resorption rates, and immune parameters (cytokine levels and splenic/lymph node/placental immune cell subsets) were analyzed. Joint pathology was evaluated via histology (HE is staining) and anti-CCP antibody levels. Flow cytometry was used to analyze immune populations within the spleen along with the associated lymphatic nodes. <b>Results:</b> Synovial hyperplasia, elevated anti-CCP, and systemic inflammation were all observed in IA mice. Compared to controls, IA mice demonstrated a reduced mating success rate, prolonged conception time, decreased pregnancy rates, and increased embryo resorption. IA mice showed elevated Th1/Th17 cytokines-IFN-γ, TNF-α, and IL-17, and an expansion of pro-inflammatory immune cells, including NK cells, CD11b+ myeloid cells, neutrophils, M1 macrophages, and Tc1, in the spleen/lymph nodes. Placental immune dysregulation featured increased NKT, NK, and CD4+ cell infiltration. Conversely, anti-inflammatory subsets, such as M2 macrophages and dendritic cells, were reduced. <b>Conclusions:</b> IA increased APOs and skewed the immune microenvironment toward a pro-inflammatory state dominated by Th1/Th17/Tc1 responses and cytotoxic cell activation. These findings highlight immune dysregulation as a key driver of IA-associated pregnancy complications, providing mechanistic insights for therapeutic intervention. |
| format | Article |
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| institution | OA Journals |
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| language | English |
| publishDate | 2025-06-01 |
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| series | Biomedicines |
| spelling | doaj-art-1277755a368b4b31a9112510701aea212025-08-20T02:24:41ZengMDPI AGBiomedicines2227-90592025-06-01136144010.3390/biomedicines13061440Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine ModelChenxi Yang0Wenjuan Li1Xinxin Liu2Zijun Ma3Jun Chen4Quan Gong5Zachary Braunstein6Xiaoquan Rao7Yingying Wei8Jixin Zhong9Division of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDivision of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDivision of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDivision of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaHubei Clinical Research Center of Hypertension, Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Sinopharm Dongfeng General Hospital, Hubei University of Medicine, Shiyan 442000, ChinaDepartment of Immunology, School of Medicine, Yangtze University, Jingzhou 434023, ChinaDivision of Hematology, Department of Internal Medicine, James Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USADivision of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDivision of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, ChinaDivision of Rheumatology and Immunology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China<b>Objective<b>:</b></b> Inflammatory arthritis (IA) has been linked to a number of adverse pregnancy outcomes (APOs), but the mechanisms linking IA-related immune dysregulation to compromised reproductive success remain poorly understood. This project will examine how IA affects pregnancy outcomes and alters the associated immune microenvironment using SKG (ZAP70<sup>W163C</sup>) mice, a mouse model that suffers from arthritis resembling human IA. <b>Methods:</b> IA was induced in SKG mice on a C57BL/6J background via mannan exposure. Wild-type C57BL/6 mice served as controls. Pregnancy rates, conception time, embryo resorption rates, and immune parameters (cytokine levels and splenic/lymph node/placental immune cell subsets) were analyzed. Joint pathology was evaluated via histology (HE is staining) and anti-CCP antibody levels. Flow cytometry was used to analyze immune populations within the spleen along with the associated lymphatic nodes. <b>Results:</b> Synovial hyperplasia, elevated anti-CCP, and systemic inflammation were all observed in IA mice. Compared to controls, IA mice demonstrated a reduced mating success rate, prolonged conception time, decreased pregnancy rates, and increased embryo resorption. IA mice showed elevated Th1/Th17 cytokines-IFN-γ, TNF-α, and IL-17, and an expansion of pro-inflammatory immune cells, including NK cells, CD11b+ myeloid cells, neutrophils, M1 macrophages, and Tc1, in the spleen/lymph nodes. Placental immune dysregulation featured increased NKT, NK, and CD4+ cell infiltration. Conversely, anti-inflammatory subsets, such as M2 macrophages and dendritic cells, were reduced. <b>Conclusions:</b> IA increased APOs and skewed the immune microenvironment toward a pro-inflammatory state dominated by Th1/Th17/Tc1 responses and cytotoxic cell activation. These findings highlight immune dysregulation as a key driver of IA-associated pregnancy complications, providing mechanistic insights for therapeutic intervention.https://www.mdpi.com/2227-9059/13/6/1440inflammatory arthritispregnancy outcomesSKG miceT cellsinflammatory cytokines |
| spellingShingle | Chenxi Yang Wenjuan Li Xinxin Liu Zijun Ma Jun Chen Quan Gong Zachary Braunstein Xiaoquan Rao Yingying Wei Jixin Zhong Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model Biomedicines inflammatory arthritis pregnancy outcomes SKG mice T cells inflammatory cytokines |
| title | Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model |
| title_full | Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model |
| title_fullStr | Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model |
| title_full_unstemmed | Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model |
| title_short | Immune Dysregulation at the Maternal–Fetal Interface Exacerbates Adverse Pregnancy Outcomes in an Inflammatory Arthritis Murine Model |
| title_sort | immune dysregulation at the maternal fetal interface exacerbates adverse pregnancy outcomes in an inflammatory arthritis murine model |
| topic | inflammatory arthritis pregnancy outcomes SKG mice T cells inflammatory cytokines |
| url | https://www.mdpi.com/2227-9059/13/6/1440 |
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