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

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), <i>Alox15</i> (12/15-lipoxygenase), and <i>Csf1</i> (<i>colony-stimulating factor 1</i>). 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.