Neonatal imprinting of alveolar macrophages via neutrophil-derived 12-HETE.

Resident-tissue macrophages (RTM) arise from embryonic precursors 1,2 , yet developmental signals shaping their longevity remain largely unknown. Here we demonstrated in mice genetically deficient in 12/15-LOX (Alox15 -/- ) that neonatal neutrophil-derived 12-HETE was required for self-renewal and maintenance of alveolar macrophages (AM) during lung development. Although the seeding and differentiation of AM progenitors remained intact, the absence of 12-HETE led to a significant reduction of AM in the adult lungs and enhanced senescence due to increased prostaglandin E 2 (PGE 2 ) production. A compromised AM compartment resulted in increased susceptibility to LPS-induced acute lung injury, pulmonary influenza A virus and SARS-CoV-2 infections. Our results highlight the complexity of prenatal RTM programming and reveal their dependency on in trans eicosanoid production by neutrophils for lifelong self-renewal.