Siglec-F+ neutrophils promote the resolution of acute lung injury through ALOX15 induction

Sci Immunol. 2025 Dec 19;10(114):eaeb2657. doi: 10.1126/sciimmunol.aeb2657. Epub 2025 Dec 19.

Abstract

Neutrophils have vital proinflammatory protective functions, but gene expression changes in neutrophils found in inflamed tissues suggest additional proresolving effects. We identified a neutrophil subset with a distinct phenotype and function that emerges in mouse lungs during resolution of injury. These resolution-phase neutrophils increased expression of Siglec-F (sialic acid-binding Ig-like lectin F), Alox15 (12/15-lipoxygenase), and Csf1 (colony-stimulating factor 1). Siglec-F+ neutrophils promoted macrophage differentiation and produced specialized proresolving mediators that accelerated injury resolution. Neutrophil depletion hindered lung epithelial catabatic responses, whereas adoptive transfer of Siglec-F+ neutrophils accelerated restitution of lung epithelial cells. Transforming growth factor-β (TGF-β) and granulocyte-macrophage colony-stimulating factor (GM-CSF), acting via activator protein-1 (AP-1)/Jun, promoted expression of Siglec-F in mouse neutrophils and ALOX15 in mouse and human neutrophils. In patients with respiratory failure, ALOX15+ neutrophils were present in the bronchoalveolar lavage samples, and their frequency correlated with improved oxygenation. Thus, Siglec-F+ ALOX15+ proresolving neutrophils contribute to tissue injury responses.

MeSH terms

  • Acute Lung Injury* / immunology
  • Animals
  • Arachidonate 12-Lipoxygenase* / metabolism
  • Arachidonate 15-Lipoxygenase* / metabolism
  • Disease Models, Animal
  • Epithelial Cells
  • Humans
  • Macrophages / immunology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Neutrophils* / immunology
  • Sialic Acid Binding Immunoglobulin-like Lectins / metabolism

Substances

  • Alox15 protein, mouse
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase
  • Siglecf protein, mouse
  • Sialic Acid Binding Immunoglobulin-like Lectins