Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis
Abstract Background Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2023-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-023-02829-3 |
| _version_ | 1827916762055704576 |
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| author | Xiuxing Liu Chenyang Gu Jianjie Lv Qi Jiang Wen Ding Zhaohao Huang Yidan Liu Yuhan Su Chun Zhang Zhuping Xu Xianggui Wang Wenru Su |
| author_facet | Xiuxing Liu Chenyang Gu Jianjie Lv Qi Jiang Wen Ding Zhaohao Huang Yidan Liu Yuhan Su Chun Zhang Zhuping Xu Xianggui Wang Wenru Su |
| author_sort | Xiuxing Liu |
| collection | DOAJ |
| description | Abstract Background Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear. Methods To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing. Results We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD. Conclusions Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases. |
| first_indexed | 2024-03-13T03:19:52Z |
| format | Article |
| id | doaj.art-237d27220310489b8bb253ac27fe88be |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-03-13T03:19:52Z |
| publishDate | 2023-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-237d27220310489b8bb253ac27fe88be2023-06-25T11:23:27ZengBMCJournal of Neuroinflammation1742-20942023-06-0120111910.1186/s12974-023-02829-3Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axisXiuxing Liu0Chenyang Gu1Jianjie Lv2Qi Jiang3Wen Ding4Zhaohao Huang5Yidan Liu6Yuhan Su7Chun Zhang8Zhuping Xu9Xianggui Wang10Wenru Su11State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceGuangzhou Women and Children’s Medical Center, Guangzhou Medical UniversityState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceDepartment of Ophthalmology, West China Hospital, Sichuan UniversityDepartment of Ophthalmology, West China Hospital, Sichuan UniversityEye Center of Xiangya Hospital, Central South UniversityState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual ScienceAbstract Background Autoimmune uveitis (AU) is the most common ophthalmic autoimmune disease (AD) and is characterized by a complex etiology, high morbidity, and high rate of blindness. AU remission has been observed in pregnant female patients. However, the effects of progesterone (PRG), a critical hormone for reproduction, on the treatment of AU and the regulatory mechanisms remain unclear. Methods To this end, we established experimental autoimmune uveitis (EAU) animal models and constructed a high-dimensional immune atlas of EAU-model mice undergoing PRG treatment to explore the underlying therapeutic mechanisms of PRG using single-cell RNA sequencing. Results We found that PRG ameliorated retinal lesions and inflammatory infiltration in EAU-model mice. Further single-cell analysis indicated that PRG reversed the EAU-induced expression of inflammatory genes (AP-1 family, S100a family, and Cxcr4) and pathological processes related to inflammatory cell migration, activation, and differentiation. Notably, PRG was found to regulate the Th17/Treg imbalance by increasing the reduced regulatory functional mediators of Tregs and diminishing the overactivation of pathological Th17 cells. Moreover, the Id2/Pim1 axis, IL-23/Th17/GM-CSF signaling, and enhanced Th17 pathogenicity during EAU were reversed by PRG treatment, resulting in the alleviation of EAU inflammation and treatment of AD. Conclusions Our study provides a comprehensive single-cell map of the immunomodulatory effects of PRG therapy on EAU and elaborates on the possible therapeutic mechanisms, providing novel insights into its application for treating autoimmune diseases.https://doi.org/10.1186/s12974-023-02829-3ProgesteroneAutoimmune uveitisSingle-cell RNA sequencingTh17 cellsId2Treg |
| spellingShingle | Xiuxing Liu Chenyang Gu Jianjie Lv Qi Jiang Wen Ding Zhaohao Huang Yidan Liu Yuhan Su Chun Zhang Zhuping Xu Xianggui Wang Wenru Su Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis Journal of Neuroinflammation Progesterone Autoimmune uveitis Single-cell RNA sequencing Th17 cells Id2 Treg |
| title | Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis |
| title_full | Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis |
| title_fullStr | Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis |
| title_full_unstemmed | Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis |
| title_short | Progesterone attenuates Th17-cell pathogenicity in autoimmune uveitis via Id2/Pim1 axis |
| title_sort | progesterone attenuates th17 cell pathogenicity in autoimmune uveitis via id2 pim1 axis |
| topic | Progesterone Autoimmune uveitis Single-cell RNA sequencing Th17 cells Id2 Treg |
| url | https://doi.org/10.1186/s12974-023-02829-3 |
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