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Identification of pharmacologic inhibitors and activators of IL-4-induced macrophage polarization

ABSTRACT: Macrophages polarize towards different subpopulations with distinct and partly antagonistic functions in various diseases. IFNγ/LPS-polarized M1-type macrophages can have antiangiogenic activity, whereas IL-4-induced M2-type macrophages can be proangiogenic and profibrotic. Therapeutic strategies to inhibit M2-type polarization while promoting M1-type polarization could serve to inhibit pathological angiogenesis and fibrosis. Here, by combining global quantitative time-course proteomics and phosphoproteomics with a small-molecule inhibitor screen we identify signaling events that promote specifically IL-4-induced and not IFNγ/LPS-induced macrophage polarization and found that the MEK inhibitor trametinib and the HDAC inhibitor panobinostat potently prevent M2-type macrophage polarization without inhibiting M1-type polarization. In contrast, selective B-Raf inhibition promotes M2-type polarization. Trametinib and panobinostat also blocked M2-type macrophage polarization and concomitantly angiogenesis and fibrosis in models of wound healing and neovascular age-related macular degeneration in vivo. Thus, these pharmacologic inhibitors could be utilized therapeutically to selectively block IL4-induced macrophage polarization and reduce pathologic angiogenesis and fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE140235 | GEO | 2021/10/01

REPOSITORIES: GEO

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