ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1618135
VISTA Acts as a Protective Immune Checkpoint in Indirect Acute Respiratory Distress Syndrome by Modulating Systemic and Compartmentalized Inflammation
Provisionally accepted
- 1University of Shanghai for Science and Technology, Shanghai, Shanghai Municipality, China
- 2Shanghai Pudong Hospital, Shanghai, Shanghai Municipality, China
- 3Shanghai General Hospital, Shanghai, China
- 4Rhode Island Hospital, Providence, Rhode Island, United States
- 5Gongli Hospital, Second Military Medical University, Shanghai, China
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Background: Indirect acute respiratory distress syndrome (iARDS) is a life-threatening inflammatory lung injury often triggered by extrapulmonary insults. While immune checkpoints are critical regulators of inflammation, the role of V-domain Ig suppressor of T cell activation (VISTA) in iARDS remains unexplored. Methods: Using a murine model of iARDS, we compared outcomes in VISTA knockout (VISTA -/-) and wild-type mice. Disease severity was assessed via 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). Results: VISTA -/-mice exhibited exacerbated lung injury, reduced survival, and elevated systemic levels of IL-6, IL-10, MIP-2, and KC compared to wild-type controls. While lung tissue cytokines 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. Conclusion: Our findings establish VISTA as a protective immune checkpoint in iARDS, restraining systemic hyperinflammation and organ damage. While antibodymediated VISTA targeting altered inflammatory pathways, its incomplete efficacy suggests complex, multifactorial mechanisms. These results position VISTA as a novel therapeutic target for iARDS, warranting further exploration of timed immunomodulatory strategies to harness its protective effects.
Keywords: Vista, indirect ARDS, Immune checkpoint, Cytokine storm, Myeloid Cells, compartmentalized inflammation
Received: 25 Apr 2025; Accepted: 03 Jun 2025.
Copyright: © 2025 Hu, Jiang, Chung, Gray, Chen, Guo and Ayala. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Baoji Hu, University of Shanghai for Science and Technology, Shanghai, 130012, Shanghai Municipality, China
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