Alveolar macrophages rely on GM-CSF from alveolar epithelial type 2 cells before and after birth

J Exp Med. 2021 Oct 4;218(10):e20210745. doi: 10.1084/jem.20210745. Epub 2021 Aug 25.


Programs defining tissue-resident macrophage identity depend on local environmental cues. For alveolar macrophages (AMs), these signals are provided by immune and nonimmune cells and include GM-CSF (CSF2). However, evidence to functionally link components of this intercellular cross talk remains scarce. We thus developed new transgenic mice to profile pulmonary GM-CSF expression, which we detected in both immune cells, including group 2 innate lymphoid cells and γδ T cells, as well as AT2s. AMs were unaffected by constitutive deletion of hematopoietic Csf2 and basophil depletion. Instead, AT2 lineage-specific constitutive and inducible Csf2 deletion revealed the nonredundant function of AT2-derived GM-CSF in instructing AM fate, establishing the postnatal AM compartment, and maintaining AMs in adult lungs. This AT2-AM relationship begins during embryogenesis, where nascent AT2s timely induce GM-CSF expression to support the proliferation and differentiation of fetal monocytes contemporaneously seeding the tissue, and persists into adulthood, when epithelial GM-CSF remains restricted to AT2s.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Cell Differentiation
  • Cytokines / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Granulocyte-Macrophage Colony-Stimulating Factor / genetics
  • Granulocyte-Macrophage Colony-Stimulating Factor / physiology*
  • Immunity, Innate
  • Lung / cytology*
  • Lung / embryology
  • Macrophages, Alveolar / cytology
  • Macrophages, Alveolar / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic


  • Cytokines
  • Granulocyte-Macrophage Colony-Stimulating Factor