Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus
Abstract Background The small intestine harbors a rich array of intestinal intraepithelial lymphocytes (IELs) that interact with structural cells to collectively sustain gut immune homeostasis. Dysregulation of gut immune homeostasis was implicated in the pathogenesis of multiple autoimmune diseases...
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BMC
2025-01-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06147-5 |
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| author | Qiaolin Wang Yutong Wu Lianlian Ouyang Xiaoli Min Meiling Zheng Lingyu Gao Xiaoyun Chen Zhi Hu Shuang Yang Wenjuan Jiang Sujie Jia Qianjin Lu Ming Zhao |
| author_facet | Qiaolin Wang Yutong Wu Lianlian Ouyang Xiaoli Min Meiling Zheng Lingyu Gao Xiaoyun Chen Zhi Hu Shuang Yang Wenjuan Jiang Sujie Jia Qianjin Lu Ming Zhao |
| author_sort | Qiaolin Wang |
| collection | DOAJ |
| description | Abstract Background The small intestine harbors a rich array of intestinal intraepithelial lymphocytes (IELs) that interact with structural cells to collectively sustain gut immune homeostasis. Dysregulation of gut immune homeostasis was implicated in the pathogenesis of multiple autoimmune diseases, however, whether this homeostasis is disrupted in a lupus autoimmune background remains unclear. Methods We performed single-cell RNA sequencing (scRNA-seq) analyses to elucidate immune and structural milieu in the intestinal epithelium of MRL/Lpr lupus mice (Lpr mice) and MRL/Mpj control mice (Mpj mice). Comprehensive analyses including unsupervised clustering, trajectories, and cellular communication were performed. The primary findings from scRNA-seq were further validated by quantitative polymerase chain reaction (qPCR), flow cytometry, and in vivo experiments including selenium supplementation. Results We observed a significant reduction in CD8αα + IELs, accompanied by a marked increase in CD8αβ + IELs in Lpr mice. Additionally, subsets of CD8 + IELs exhibiting significantly enhanced effector functions were found to be markedly enriched in Lpr mice. Intercellular communication patterns within intestinal epithelial immune and structural cells were found to be specifically altered in Lpr mice. Moreover, scRNA-seq revealed significantly decreased intestinal TCRγδ T cells (γδT) associated with reduced aryl-hydrocarbon receptor repressor (AHRR) expression and subsequent oxidative stress and ferroptosis in Lpr mice. Antioxidant selenium effectively reversed the loss of γδT in Lpr mice, improved the gut barrier, and alleviated lupus symptoms. Conclusions Our high-resolution single-cell atlas enhances the understanding of the immune and structural milieu of intestinal epithelium in lupus and provides new insights into lupus pathogenesis mediated by intestinal immune dysregulation. |
| format | Article |
| id | doaj-art-b3bd7a7babe54968bd167ef160d46c3b |
| institution | Kabale University |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-b3bd7a7babe54968bd167ef160d46c3b2025-02-02T12:40:36ZengBMCJournal of Translational Medicine1479-58762025-01-0123112110.1186/s12967-025-06147-5Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosusQiaolin Wang0Yutong Wu1Lianlian Ouyang2Xiaoli Min3Meiling Zheng4Lingyu Gao5Xiaoyun Chen6Zhi Hu7Shuang Yang8Wenjuan Jiang9Sujie Jia10Qianjin Lu11Ming Zhao12Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South UniversityInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Dermatology, Hunan Key Laboratory of Medical Epigenomics, Second Xiangya Hospital, Central South UniversityInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Pharmacy, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical CollegeAbstract Background The small intestine harbors a rich array of intestinal intraepithelial lymphocytes (IELs) that interact with structural cells to collectively sustain gut immune homeostasis. Dysregulation of gut immune homeostasis was implicated in the pathogenesis of multiple autoimmune diseases, however, whether this homeostasis is disrupted in a lupus autoimmune background remains unclear. Methods We performed single-cell RNA sequencing (scRNA-seq) analyses to elucidate immune and structural milieu in the intestinal epithelium of MRL/Lpr lupus mice (Lpr mice) and MRL/Mpj control mice (Mpj mice). Comprehensive analyses including unsupervised clustering, trajectories, and cellular communication were performed. The primary findings from scRNA-seq were further validated by quantitative polymerase chain reaction (qPCR), flow cytometry, and in vivo experiments including selenium supplementation. Results We observed a significant reduction in CD8αα + IELs, accompanied by a marked increase in CD8αβ + IELs in Lpr mice. Additionally, subsets of CD8 + IELs exhibiting significantly enhanced effector functions were found to be markedly enriched in Lpr mice. Intercellular communication patterns within intestinal epithelial immune and structural cells were found to be specifically altered in Lpr mice. Moreover, scRNA-seq revealed significantly decreased intestinal TCRγδ T cells (γδT) associated with reduced aryl-hydrocarbon receptor repressor (AHRR) expression and subsequent oxidative stress and ferroptosis in Lpr mice. Antioxidant selenium effectively reversed the loss of γδT in Lpr mice, improved the gut barrier, and alleviated lupus symptoms. Conclusions Our high-resolution single-cell atlas enhances the understanding of the immune and structural milieu of intestinal epithelium in lupus and provides new insights into lupus pathogenesis mediated by intestinal immune dysregulation.https://doi.org/10.1186/s12967-025-06147-5Systemic lupus erythematosusGut immune environmentIntestinal intraepithelial lymphocyteEnterocyte |
| spellingShingle | Qiaolin Wang Yutong Wu Lianlian Ouyang Xiaoli Min Meiling Zheng Lingyu Gao Xiaoyun Chen Zhi Hu Shuang Yang Wenjuan Jiang Sujie Jia Qianjin Lu Ming Zhao Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus Journal of Translational Medicine Systemic lupus erythematosus Gut immune environment Intestinal intraepithelial lymphocyte Enterocyte |
| title | Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| title_full | Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| title_fullStr | Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| title_full_unstemmed | Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| title_short | Single-cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| title_sort | single cell analyses of intestinal epithelium reveal the dysregulation of gut immune microenvironment in systemic lupus erythematosus |
| topic | Systemic lupus erythematosus Gut immune environment Intestinal intraepithelial lymphocyte Enterocyte |
| url | https://doi.org/10.1186/s12967-025-06147-5 |
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