CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis
Abstract Background Myocarditis is a common inflammatory heart disease in children and young adults, with fulminant myocarditis (FM) being the most severe form due to its rapid onset and high mortality rate. However, the precise pathological immune subsets and molecular change in myocarditis, partic...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-04-01
|
| Series: | Journal of Translational Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12967-025-06394-6 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849765335808344064 |
|---|---|
| author | Li Zhang Keyu Liu Xiuyun Duan Shan Zhou Hailin Jia Yingnan You Bo Han |
| author_facet | Li Zhang Keyu Liu Xiuyun Duan Shan Zhou Hailin Jia Yingnan You Bo Han |
| author_sort | Li Zhang |
| collection | DOAJ |
| description | Abstract Background Myocarditis is a common inflammatory heart disease in children and young adults, with fulminant myocarditis (FM) being the most severe form due to its rapid onset and high mortality rate. However, the precise pathological immune subsets and molecular change in myocarditis, particularly FM, remain unknown. Methods We performed single-cell RNA sequencing of pediatric peripheral blood mononuclear cells during the acute and recovery phases of FM. A viral myocarditis (MC) mouse model was established using CVB3. Deletion and adoptive transfer of CD8+T cells, as well as blockade of CXCR4, were conducted in vivo. CD8+T cells were sorted and cultivated in vitro, then stimulated with CXCL12 and CXCR4 antagonists to investigate the mechanism of CD8+T cell overactivation. Results CD8+T cells show significant activation, amplification, enhanced cytotoxicity, and increased chemotactic ability in FM. Deletion of CD8+T cells alleviates myocardial injury and improves cardiac function in MC mice, while adoptive transfer of CD8+T cells from MC mice aggravates myocardial inflammation and injury. The transcriptomic analysis reveals elevated CXCR4 expression in CD8+T cells in acute FM. In vitro experiments demonstrate that the CXCL12/CXCR4 axis drives the overactivation and cytotoxicity of CD8+T cells. In vivo treatment with a CXCR4 antagonist effectively reduces CD8+T cell accumulation in the heart, alleviates myocardial inflammation, and improves cardiac function in MC mice. Conclusions These findings provide deeper insights into the immune landscape of pediatric FM, uncovering a novel role of the CXCL12/CXCR4 axis in driving CD8+T cell responses in myocarditis. Furthermore, they highlight the CXCL12/CXCR4 axis as a promising therapeutic target for myocarditis treatment. |
| format | Article |
| id | doaj-art-7df25da8b7264f2aa48a875186c1d0c8 |
| institution | DOAJ |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-7df25da8b7264f2aa48a875186c1d0c82025-08-20T03:04:53ZengBMCJournal of Translational Medicine1479-58762025-04-0123111910.1186/s12967-025-06394-6CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditisLi Zhang0Keyu Liu1Xiuyun Duan2Shan Zhou3Hailin Jia4Yingnan You5Bo Han6Department of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatric Cardiology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong UniversityDepartment of Pediatric Cardiology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong UniversityShandong First Medical University & Shandong Academy of Medical SciencesDepartment of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityDepartment of Pediatric Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical UniversityAbstract Background Myocarditis is a common inflammatory heart disease in children and young adults, with fulminant myocarditis (FM) being the most severe form due to its rapid onset and high mortality rate. However, the precise pathological immune subsets and molecular change in myocarditis, particularly FM, remain unknown. Methods We performed single-cell RNA sequencing of pediatric peripheral blood mononuclear cells during the acute and recovery phases of FM. A viral myocarditis (MC) mouse model was established using CVB3. Deletion and adoptive transfer of CD8+T cells, as well as blockade of CXCR4, were conducted in vivo. CD8+T cells were sorted and cultivated in vitro, then stimulated with CXCL12 and CXCR4 antagonists to investigate the mechanism of CD8+T cell overactivation. Results CD8+T cells show significant activation, amplification, enhanced cytotoxicity, and increased chemotactic ability in FM. Deletion of CD8+T cells alleviates myocardial injury and improves cardiac function in MC mice, while adoptive transfer of CD8+T cells from MC mice aggravates myocardial inflammation and injury. The transcriptomic analysis reveals elevated CXCR4 expression in CD8+T cells in acute FM. In vitro experiments demonstrate that the CXCL12/CXCR4 axis drives the overactivation and cytotoxicity of CD8+T cells. In vivo treatment with a CXCR4 antagonist effectively reduces CD8+T cell accumulation in the heart, alleviates myocardial inflammation, and improves cardiac function in MC mice. Conclusions These findings provide deeper insights into the immune landscape of pediatric FM, uncovering a novel role of the CXCL12/CXCR4 axis in driving CD8+T cell responses in myocarditis. Furthermore, they highlight the CXCL12/CXCR4 axis as a promising therapeutic target for myocarditis treatment.https://doi.org/10.1186/s12967-025-06394-6MyocarditisSingle-cell RNA sequencingCXCR4CD8+T cell |
| spellingShingle | Li Zhang Keyu Liu Xiuyun Duan Shan Zhou Hailin Jia Yingnan You Bo Han CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis Journal of Translational Medicine Myocarditis Single-cell RNA sequencing CXCR4 CD8+T cell |
| title | CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis |
| title_full | CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis |
| title_fullStr | CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis |
| title_full_unstemmed | CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis |
| title_short | CXCL12/CXCR4 axis mediates CD8 + T cell overactivation in the progression of viral myocarditis |
| title_sort | cxcl12 cxcr4 axis mediates cd8 t cell overactivation in the progression of viral myocarditis |
| topic | Myocarditis Single-cell RNA sequencing CXCR4 CD8+T cell |
| url | https://doi.org/10.1186/s12967-025-06394-6 |
| work_keys_str_mv | AT lizhang cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT keyuliu cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT xiuyunduan cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT shanzhou cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT hailinjia cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT yingnanyou cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis AT bohan cxcl12cxcr4axismediatescd8tcelloveractivationintheprogressionofviralmyocarditis |