TGF-β–PDL1 signaling in neutrophils preserves the lung barrier during hyperinflammation

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.