Scientists pinpoint why alveolar macrophages don’t develop properly

By The Science Advisory Board staff writers

September 19, 2022 -- Researchers in Germany have solved the mystery of what prevents alveolar macrophages from developing properly: the transcription factor CCAAT/enhancer binding protein beta (C/EBPβ).

The study team from Max-Delbrück-Center for Molecular Medicine in Helmholtz Association (MDC) in Berlin isolated alveolar macrophages from healthy mice and from those lacking the C/EBPβ gene. They conducted in vitro tests on those immune cells as well as various genome and transcriptome analyses of freshly isolated cells, specifically transcriptomic, ChIPmentation, and chromatin accessibility analysis (Science Immunology, September 16, 2022).

The macrophages of healthy mice performed their tasks properly whereas those extracted from the genetically modified mice took up and stored many lipids. However, the genetically modified macrophages were unable to digest the lipids and instead swelled up into so-called "foam cells" and soon perished, redepositing the ingested lipids.

The same phenomenon has been observed by doctors treating the lung disease pulmonary alveolar proteinosis. In addition, the defective macrophages proved barely able to proliferate.

The scientists also observed that the long C/EBPβ protein variants LAP* and LAP, combined with colony-stimulating factor 2 (CSF2) signaling, induced specific expression of Pparg isoform 2, which is a mechanism observed in other CSF2-primed macrophages. These findings indicate that C/EBPβ is a key regulator of alveolar macrophage development and lipid metabolism.

The signaling pathway of the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) could shed light on other lipid-related diseases such as atherosclerosis and morbid obesity, the authors said.

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