Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE
Erwan Pernet, Sarah Sun, Nicole Sarden, Saideep Gona, Angela Nguyen, Nargis Khan, Martin Mawhinney, Kim A. Tran, Julia Chronopoulos, Dnyandeo Amberkar, Mina Sadeghi, Alexandre Grant, Shradha Wali, Renaud Prével, Jun Ding, James G. Martin, Ajitha Thanabalasuriar, Bryan G. Yipp, Luis B. Barreiro, Maziar Divangahi
Abstract
Abstract Resident-tissue macrophages (RTMs) arise from embryonic precursors 1,2 , 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 E 2 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.