TGF-β–PDL1 signaling in neutrophils preserves the lung barrier during hyperinflammation
13 affiliations
- 1Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada
- 2Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA
- 3Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA
- 4Division of Computational Medicine, Department of Medicine, Stanford University, Stanford, CA
- 5Department of Physiology, McGill University, Montreal, QC, Canada
- 6Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- 7Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- 8Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, QC, Canada
- 9Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
- 10Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
- 11Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
- 12Vaccine and Immune Therapies, BioPharmaceuticals Research & Development Center, AstraZeneca, Gaithersburg, MD
- 13Department of Bioengineering, McGill University, Montreal, QC, Canada
Abstract
The hyperinflammatory syndromes in patients who are critically ill, including those with trauma injury, sepsis, and acute lung injury, are characterized by dysregulated neutrophil responses that contribute to tissue damage and poor outcomes. Using murine models of cytokine storm induced by trauma and lung injury, we identified transforming growth factor β (TGF-β) as a central regulator of immune checkpoints in neutrophils. TGF-β signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGF-β signaling during hyperinflammation restores the migratory capacity of neutrophils but leads to excessive activation, severe pulmonary tissue damage, and increased susceptibility to spontaneous bacterial infection in the lung. Mechanistically, PDL1 expression alters neutrophil behavior within lung capillaries, promoting intravascular clustering and restricting tissue infiltration. Targeted deletion of PDL1 in neutrophils reverses hyperinflammation-induced clustering, restores effective trafficking to infectious foci, and enhances host-protective immune function while limiting pathological neutrophil hyperactivation. These findings define a TGF-β–PDL1 regulatory axis that restrains the pathogenicity of neutrophils during hyperinflammation, revealing a checkpoint mechanism that balances host defense and tissue integrity.
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BibTeX
@article{li2026tgfβpdl1,
title = {{TGF-β–PDL1 signaling in neutrophils preserves the lung barrier during hyperinflammation}},
author = {Ziyi Li and Andrew R. Moore and Hong Zheng and Janmes Karunamurthy and Aanya Bhagrath and Jiangxue Li and Daniel Young and Leonardo F. Jurado and Katalina Couto and Amelia Kulle and Haley Park and Ashley Kwak and Vaishnav Belur and Sebastien Talbot and Maziar Divangahi and Antonio DiGiandomenico and Angela Rogers and Taylor S. Cohen and Allen J. Ehrlicher and Judith N. Mandl and Jing Wang and Antoine Dufour and Purvesh Khatri and Ajitha Thanabalasuriar},
journal = {Blood},
year = {2026},
month = may,
doi = {10.1182/blood.2025031635},
url = {https://doi.org/10.1182/blood.2025031635},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - TGF-β–PDL1 signaling in neutrophils preserves the lung barrier during hyperinflammation
AU - Ziyi Li
AU - Andrew R. Moore
AU - Hong Zheng
AU - Janmes Karunamurthy
AU - Aanya Bhagrath
AU - Jiangxue Li
AU - Daniel Young
AU - Leonardo F. Jurado
AU - Katalina Couto
AU - Amelia Kulle
AU - Haley Park
AU - Ashley Kwak
AU - Vaishnav Belur
AU - Sebastien Talbot
AU - Maziar Divangahi
AU - Antonio DiGiandomenico
AU - Angela Rogers
AU - Taylor S. Cohen
AU - Allen J. Ehrlicher
AU - Judith N. Mandl
AU - Jing Wang
AU - Antoine Dufour
AU - Purvesh Khatri
AU - Ajitha Thanabalasuriar
PY - 2026
DA - 2026/05/22
JO - Blood
DO - 10.1182/blood.2025031635
UR - https://doi.org/10.1182/blood.2025031635
AB - The hyperinflammatory syndromes in patients who are critically ill, including those with trauma injury, sepsis, and acute lung injury, are characterized by dysregulated neutrophil responses that contribute to tissue damage and poor outcomes. Using murine models of cytokine storm induced by trauma and lung injury, we identified transforming growth factor β (TGF-β) as a central regulator of immune checkpoints in neutrophils. TGF-β signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGF-β signaling during hyperinflammation restores the migratory capacity of neutrophils but leads to excessive activation, severe pulmonary tissue damage, and increased susceptibility to spontaneous bacterial infection in the lung. Mechanistically, PDL1 expression alters neutrophil behavior within lung capillaries, promoting intravascular clustering and restricting tissue infiltration. Targeted deletion of PDL1 in neutrophils reverses hyperinflammation-induced clustering, restores effective trafficking to infectious foci, and enhances host-protective immune function while limiting pathological neutrophil hyperactivation. These findings define a TGF-β–PDL1 regulatory axis that restrains the pathogenicity of neutrophils during hyperinflammation, revealing a checkpoint mechanism that balances host defense and tissue integrity.
SN - 0006-4971
SN - 1528-0020
ER -