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

Abstract

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.

Early treatment with inhaled GM-CSF improves oxygenation and anti-viral immunity in COVID-19 induced lung injury – a randomized clinical trial

“…By comparing scRNAseq and CITEseq data from COVID-19 lung samples with mini-bulk transcriptomic data of the various stages of fetal and postnatal AM development in wild type mice and GM-CSF-deficient mice, we found that recruited lung macrophages in COVID-19 lungs lack GM-CSF instruction. GM-CSF is the prime cytokine of the alveolar niche, produced by type II alveolar epithelial cells (AEC) 6 . This cytokine induces the master lipid-handling transcription factor PPARγ, and causes fetal and adult monocytes to differentiate into tissue resident AMs 5,7,41 .…”

“…This cytokine induces the master lipid-handling transcription factor PPARγ, and causes fetal and adult monocytes to differentiate into tissue resident AMs 5,7,41 . In adult mice, the return of tissue resident AMs following their depletion by infectious insults depends on GM-CSF production by type II AECs 6,56 . We have tried to measure GM-CSF levels in the BAL fluid of COVID-19 patients and other pulmonary infections but failed to detect it (data not shown), and serum levels of GM-CSF were very low in our cohort, despite an earlier report 45 .…”

“…We next aimed to unravel the mechanisms hampering monocyte to AM instruction during COVID-19. To more closely understand AM development, we turned to the mouse model, where the various stages of AM development from fetal monocytes and AM instruction by epithelial cell derived GM-CSF (encoded by the Csf2 gene) have been closely described by us and others [5][6][7]41 . We sorted lung monocyte and developing AM populations from lung tissue of wild-type mice at different time points from embryonic day 15 until adulthood and performed transcriptional micro-array analysis on these developmental stages (Fig.…”

“…Tissue resident AM develop early in life, and can occupy the alveolar niche through local low-grade proliferation without the need for replenishment by circulating monocytes 5 . Within the first week of life, alveolar epithelial-cell derived granulocyte-macrophage colony stimulating factor (GM-CSF) provides the instructive signal that programs fetal monocytes to become homeostatic tissue-resident AMs in the alveolar niche [5][6][7][8][9] . These resident AMs then self-maintain with only minimal input from circulating monocytes in both mouse 5,10,11 and human [12][13][14] .…”

Alveolar Macrophages: Adaptation to Their Anatomic Niche during and after Inflammation

“…The observation that all embryonic macrophage populations (yolk sac-derived, fetal liver-derived, and bone marrow-derived) can independently colonize an empty alveolar niche and differentiate into functional AM suggests that the lung tissue produces maturation and development signals that can turn embryonic progenitors into differentiated AM. In this setting, the production of granulocyte macrophage colony-stimulating factor (GM-CSF) by the lung stroma, specifically by the alveolar epithelial type 2 cells [14], is vital since it induces the expression of the transcription factor peroxisome proliferator-activated receptor gamma (PPARG), a transcription factor essential for the differentiation and perinatal development of AM [15]. The role of GM-CSF is also supported by the demonstration that, in a situation of competition between progenitors, fetal liver progenitors, which have the highest affinity and avidity for this growth factor, become the main contributor to the replenishment of the alveolar niche [8].…”