VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation
BackgroundIndirect acute respiratory distress syndrome (iARDS) is a life-threatening inflammatory lung injury often triggered by extrapulmonary insults. Although immune checkpoints are critical regulators of inflammation, the role of V-domain Ig suppressor of T-cell activation (VISTA) in iARDS remai...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618135/full |
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| author | Baoji Hu Baoji Hu Baoji Hu Chun-Shiang Chung Chyna Gray Yaping Chen Jihong Jiang Jihong Jiang Jianrong Guo Jianrong Guo Alfred Ayala |
| author_facet | Baoji Hu Baoji Hu Baoji Hu Chun-Shiang Chung Chyna Gray Yaping Chen Jihong Jiang Jihong Jiang Jianrong Guo Jianrong Guo Alfred Ayala |
| author_sort | Baoji Hu |
| collection | DOAJ |
| description | BackgroundIndirect acute respiratory distress syndrome (iARDS) is a life-threatening inflammatory lung injury often triggered by extrapulmonary insults. Although immune checkpoints are critical regulators of inflammation, the role of V-domain Ig suppressor of T-cell activation (VISTA) in iARDS remains unexplored.MethodsUsing a murine model of iARDS, we compared outcomes in VISTA knockout (VISTA−/−) and wild-type mice. Disease severity was assessed through lung injury scoring, survival analysis, and cytokine/chemokine profiling in plasma, lung tissue, and peritoneal fluid. The therapeutic potential of VISTA was evaluated using an anti-VISTA antibody (13F3).ResultsVISTA−/− mice exhibited exacerbated lung injury, reduced survival, and elevated systemic levels of interleukin (IL)-6, IL-10, MIP-2, and KC compared to wild-type controls. While cytokine levels in lung tissue remained stable, peritoneal fluid mediators were dysregulated in VISTA−/− mice, highlighting compartment-specific inflammatory regulation. Treatment with 13F3 reduced VISTA expression on myeloid and structural cells (monocytes, neutrophils, macrophages, epithelium, endothelium) and partially modulated cytokine/chemokine profiles across compartments.ConclusionOur findings establish VISTA as a protective immune checkpoint in iARDS that restrains systemic hyperinflammation and organ damage. Although antibody-mediated VISTA targeting altered inflammatory pathways, its incomplete efficacy suggests complex, multifactorial mechanisms at play. These results position VISTA as a novel therapeutic target for iARDS and warrant further exploration of timed immunomodulatory strategies to harness its protective effects. |
| format | Article |
| id | doaj-art-51bc6253f78a4d7983a2455de1cae668 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-51bc6253f78a4d7983a2455de1cae6682025-08-20T03:28:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-07-011610.3389/fimmu.2025.16181351618135VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammationBaoji Hu0Baoji Hu1Baoji Hu2Chun-Shiang Chung3Chyna Gray4Yaping Chen5Jihong Jiang6Jihong Jiang7Jianrong Guo8Jianrong Guo9Alfred Ayala10School of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai, ChinaDepartment of Anesthesiology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, ChinaDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesDepartment of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaSchool of Gongli Hospital Medical Technology, University of Shanghai for Science and Technology, Shanghai, ChinaDepartment of Anesthesiology, Shanghai Gongli Hospital, Naval Military Medical University, Shanghai, ChinaDivision of Surgical Research, Department of Surgery, Rhode Island Hospital/The Warren Alpert School at Medicine at Brown University, Providence, RI, United StatesBackgroundIndirect acute respiratory distress syndrome (iARDS) is a life-threatening inflammatory lung injury often triggered by extrapulmonary insults. Although immune checkpoints are critical regulators of inflammation, the role of V-domain Ig suppressor of T-cell activation (VISTA) in iARDS remains unexplored.MethodsUsing a murine model of iARDS, we compared outcomes in VISTA knockout (VISTA−/−) and wild-type mice. Disease severity was assessed through lung injury scoring, survival analysis, and cytokine/chemokine profiling in plasma, lung tissue, and peritoneal fluid. The therapeutic potential of VISTA was evaluated using an anti-VISTA antibody (13F3).ResultsVISTA−/− mice exhibited exacerbated lung injury, reduced survival, and elevated systemic levels of interleukin (IL)-6, IL-10, MIP-2, and KC compared to wild-type controls. While cytokine levels in lung tissue remained stable, peritoneal fluid mediators were dysregulated in VISTA−/− mice, highlighting compartment-specific inflammatory regulation. Treatment with 13F3 reduced VISTA expression on myeloid and structural cells (monocytes, neutrophils, macrophages, epithelium, endothelium) and partially modulated cytokine/chemokine profiles across compartments.ConclusionOur findings establish VISTA as a protective immune checkpoint in iARDS that restrains systemic hyperinflammation and organ damage. Although antibody-mediated VISTA targeting altered inflammatory pathways, its incomplete efficacy suggests complex, multifactorial mechanisms at play. These results position VISTA as a novel therapeutic target for iARDS and warrant further exploration of timed immunomodulatory strategies to harness its protective effects.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618135/fullVISTAindirect ARDSimmune checkpointcytokine stormmyeloid cellscompartmentalized inflammation |
| spellingShingle | Baoji Hu Baoji Hu Baoji Hu Chun-Shiang Chung Chyna Gray Yaping Chen Jihong Jiang Jihong Jiang Jianrong Guo Jianrong Guo Alfred Ayala VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation Frontiers in Immunology VISTA indirect ARDS immune checkpoint cytokine storm myeloid cells compartmentalized inflammation |
| title | VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| title_full | VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| title_fullStr | VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| title_full_unstemmed | VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| title_short | VISTA functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| title_sort | vista functions as a protective immune checkpoint in indirect acute respiratory distress syndrome by modulating systemic and compartmentalized inflammation |
| topic | VISTA indirect ARDS immune checkpoint cytokine storm myeloid cells compartmentalized inflammation |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1618135/full |
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