Neutrophil-induced lipoxygenase subtype promotes resolution of acute lung injury in mice

Neutrophils are first responders to injury, playing a crucial role in mediating early inflammation. Recently, additional roles for neutrophils have been postulated in tissue repair and resolution of inflammation. Here, we identified a distinct subset of SiglecF+ neutrophils that emerged during mouse lung injury resolution that expressed 12/15-lipoxygenase. These SiglecF+ neutrophils demonstrated distinct anatomic distribution, morphology, gene expression and cell function compared to eosinophils and other neutrophil subsets. Notably, SiglecF+ neutrophils produced specialized pro-resolving mediators (SPMs) and macrophage colony-stimulating factor (M-CSF) that promoted monocyte differentiation into keratinocyte growth factor expressing-macrophages. Depletion of neutrophils hindered alveolar epithelial cell type II (AT2) repair, while adoptive transfer of SiglecF+ neutrophils accelerated epithelial restitution. Furthermore, TGF-b and GM-CSF, acting via AP-1/Jun, promoted SiglecF and 12/15-lipoxygenase expression in mouse neutrophils, and 15-lipoxygenase-1 in human neutrophils. Frequency of BAL 15-lipoxygenase+ neutrophils positively correlated with PaO2/FiO2 in ICU patients. Administration of 15-lipoxygenase-derived SPMs accelerated injury resolution and repair. Together, these findings uncover a pro-resolving subtype of neutrophils that play a pivotal role in the resolution of tissue injury.