Fetal monocytes possess increased metabolic capacity and replace primitive macrophages in tissue macrophage development

We studied alveolar macrophage (AM) development after single and competitive transplantation of different precursors from YS, fetal liver, and lung into neonatal Csf2ra-/- mice, which lack endogenous AM. Fetal monocytes, promoted by Myb, outcompeted primitive MF (pMF) in empty AM niches and preferentially developed to mature AM, which is associated with enhanced mitochondrial respiratory and glycolytic capacity and repression of the transcription factors c-Maf and MafB. Interestingly, AM derived from pMF failed to efficiently clear alveolar proteinosis and protect from fatal lung failure following influenza virus infection. Thus, our data demonstrate superior developmental and functional capacity of fetal monocytes over pMF in AM development and underlying mechanisms explaining replacement of pMF in fetal tissues. Overall design: single and competitive transplantation of different precursors from YS, fetal liver, and lung into neonatal Csf2ra-/- mice, which lack endogenous AM