Transcriptomics Of Monocyte-Derived Satiated Macrophages

Introduction: Monocyte-derived macrophages are readily differentiating cells that adapt their gene expression profile to environmental ques and functional needs. Engulfment of apoptotic leukocytes (efferocytosis) by macrophages during the resolution of inflammation is essential for tissue homeostasis and results in macrophage reprogramming/immune-silencing. During the resolution of inflammation, monocytes initially differentiate into reparative phagocytic macrophages and later into pro-resolving satiated macrophages that produce high levels of IFNβ to boost resolutive events.

Materials and methods: Transcriptomic analysis of phagocytic and satiated macrophages was performed to reveal their unique gene expression in comparison to resident peritoneal macrophages (RPM) and monocytes, and identify gene clusters that distinguish between these phenotypes and probably confer distinct functions to these resolution-associated myeloid cells.

Results and discussion: Our analysis reveals phagocytic and satiated resolution phase macrophages express similar gene signatures that distinct them from other myeloid cells. Moreover, we confirm these macrophages express closer transcriptomes to monocytes than to RPM. A comparison between these subsets indicated satiated macrophages down-regulate gene clusters associated with excessive tissue repair and fibrosis, ROS and NO synthesis, glycolysis, and blood vessel morphogenesis. On the other hand, satiated macrophages enhance the expression of genes associated with migration, oxidative phosphorylation, and mitochondrial fission as well as anti-viral responses when compared to phagocytic macrophages. Notably, conversion from phagocytic to satiated macrophages is associated with a reduction in the expression of extracellular matrix constituents that were demonstrated to be associated with Idiopathic Pulmonary Fibrosis.

Conclusion: Macrophage satiation during the resolution of inflammation seems to bring about a transcriptomic transition that resists tissue fibrosis and oxidative damage while promoting the restoration of tissue homeostasis to complete the resolution of inflammation.