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

Nature. 2023 Feb;614(7948):530-538. doi: 10.1038/s41586-022-05660-7. Epub 2023 Jan 4.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid* / metabolism
  • Acute Lung Injury
  • Animals
  • Animals, Newborn
  • Arachidonate 12-Lipoxygenase / deficiency
  • Arachidonate 15-Lipoxygenase / deficiency
  • COVID-19
  • Cell Self Renewal*
  • Disease Susceptibility
  • Influenza A virus
  • Lipopolysaccharides
  • Lung / cytology
  • Lung / virology
  • Macrophages, Alveolar* / cytology
  • Macrophages, Alveolar* / metabolism
  • Mice
  • Neutrophils* / metabolism
  • Orthomyxoviridae Infections
  • Prostaglandins E
  • SARS-CoV-2


  • 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid
  • Alox15 protein, mouse
  • Arachidonate 12-Lipoxygenase
  • Arachidonate 15-Lipoxygenase
  • Lipopolysaccharides
  • Prostaglandins E