Identification of a subset of lung neutrophils that promote Acute Lung Injury resolution in mice

Abstract

Abstract The acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure with limited therapeutic options. Unresolving inflammation in the lungs and alveolar-capillary barrier dysfunction are main features of ARDS. The sharp increase in the incidence of ARDS during COVID19 emphasized the need for a better understanding of immunological events in ARDS that inform novel therapeutics. Here, we used a model of self-limited acid-induced ALI by selectively instilling HCL to the left lung of adult mice. The time-course of barrier dysfunction was determined via quantification of lung consolidation by micro-computed tomography, while inflammation was assessed by histology and flow cytometry. Neutrophils, rapidly recruited into the lungs, decreased over time during resolution while macrophage numbers, reduced during initial stages, increased. Immunophenotyping of the leukocyte recruitment to the lungs during the resolution of injury uncovered a neutrophils’ subset that was expressing SiglecF. These cells were distinct from eosinophils and phenotypically, and functionally different from the classical SiglecF-negative neutrophils. The roles for SiglecF+ neutrophils were further assessed by in vitro functional studies, adoptive transfer experiments, and lipidomic analysis. Depletion of neutrophils impaired alveolar epithelial cell type II (AT2) repair, while the adoptive transfer of SiglecF+ neutrophils accelerated epithelial cell restitution. Among the mechanisms associated with the SiglecF+ neutrophils in lung repair was the production of specialized pro-resolving mediators and CSF1. In sum, we identified protective roles for a subset of tissue neutrophils during the resolution of lung injury in mice.