TGFβ-PDL1 signaling in neutrophils preserves lung barrier during hyperinflammation

The hyperinflammatory syndromes in critically ill patients, including trauma, 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 (TGFβ) as a central regulator of immune checkpoint in neutrophils. TGFβ signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGFβ 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 TGFβ-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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Journal
Blood
Published
2026-05-19
DOI
https://doi.org/10.1182/blood.2025031635
Primary Topic
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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article
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article

TGFβ-PDL1 signaling in neutrophils preserves lung barrier during hyperinflammation

Amelia Kulle, Judith N. Mandl, Jiangxue Li, Allen J. Ehrlicher et al.
Blood
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
article

TGFβ-PDL1 signaling in neutrophils preserves lung barrier during hyperinflammation

Amelia Kulle, Judith N. Mandl, Jiangxue Li, Allen J. Ehrlicher, Maziar Divangahi, Sébastien Talbot, Taylor S. Cohen, Haley Park, Hong Zheng, Ajitha Thanabalasuriar, Aanya Bhagrath, Antoine Dufour, A. R. Moore, Yi-Xiang Wang, Leonardo F. Jurado, Katalina Couto, Purvesh Khatri, A J Rogers, Janmes Karunamurthy, Antonio DiGiandomenico, Vaishnav Belur, Ziyi Li, Ashley Kwak, Daniel Young
article en

Abstract

The hyperinflammatory syndromes in critically ill patients, including trauma, 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 (TGFβ) as a central regulator of immune checkpoint in neutrophils. TGFβ signaling modulates neutrophil activation and upregulates the expression of programmed death-ligand 1 (PDL1). Disruption of TGFβ 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 TGFβ-PDL1 regulatory axis that restrains the pathogenicity of neutrophils during hyperinflammation, revealing a checkpoint mechanism that balances host defense and tissue integrity.

Blood
University of Calgary (CA), Shanghai Jiao Tong University (CN), McGill University Health Centre (CA), Karolinska Institutet (SE), AstraZeneca (United States) (US), McGill University (CA), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 8%
Neutrophil, Myeloperoxidase and Oxidative Mechanisms
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