ABSTRACT
Resident-tissue macrophages (RTMs) arise from embryonic precursors1,2, yet the developmental signals that shape their longevity remain largely unknown. Here we demonstrate in mice genetically deficient in 12-lipoxygenase and 15-lipoxygenase (Alox15-/- mice) that neonatal neutrophil-derived 12-HETE is required for self-renewal and maintenance of alveolar macrophages (AMs) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction in AMs in adult lungs and enhanced senescence owing to increased prostaglandin E2 production. A compromised AM compartment resulted in increased susceptibility to acute lung injury induced by lipopolysaccharide and to pulmonary infections with influenza A virus or SARS-CoV-2. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.
Subject(s)
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid , Cell Self Renewal , Macrophages, Alveolar , Neutrophils , Animals , Mice , 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/metabolism , Acute Lung Injury , Animals, Newborn , Arachidonate 12-Lipoxygenase/deficiency , Arachidonate 15-Lipoxygenase/deficiency , COVID-19 , Influenza A virus , Lipopolysaccharides , Lung/cytology , Lung/virology , Macrophages, Alveolar/cytology , Macrophages, Alveolar/metabolism , Neutrophils/metabolism , Orthomyxoviridae Infections , Prostaglandins E , SARS-CoV-2 , Disease SusceptibilityABSTRACT
Humans differ in their susceptibility to infectious disease, partly owing to variation in the immune response after infection. We used single-cell RNA sequencing to quantify variation in the response to influenza infection in peripheral blood mononuclear cells from European- and African-ancestry males. Genetic ancestry effects are common but highly cell type specific. Higher levels of European ancestry are associated with increased type I interferon pathway activity in early infection, which predicts reduced viral titers at later time points. Substantial population-associated variation is explained by cis-expression quantitative trait loci that are differentiated by genetic ancestry. Furthermore, genetic ancestryassociated genes are enriched among genes correlated with COVID-19 disease severity, suggesting that the early immune response contributes to ancestry-associated differences for multiple viral infection outcomes.