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

• Published in: The Journal of experimental medicine Vol. 218; no. 10
• Main Authors: Gschwend, Julia, Sherman, Samantha P.M., Ridder, Frederike, Feng, Xiaogang, Liang, Hong-Erh, Locksley, Richard M., Becher, Burkhard, Schneider, Christoph
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.10.2021
• Subjects: 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; Innate Immunity and Inflammation; Lung - cytology; Lung - embryology; Macrophages, Alveolar - cytology; Macrophages, Alveolar - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Mucosal Immunology
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20210745

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.