Macrophages polarize into distinct phenotypes in response to complex environmental cues. We found that the nuclear receptor PPARγ drove robust phenotypic changes in macrophages upon repeated stimulation with interleukin (IL)-4. The functions of PPARγ on macrophage polarization in this setting were independent of ligand binding. Ligand-insensitive PPARγ bound DNA and recruited the coactivator P300 and the architectural protein RAD21. This established a permissive chromatin environment that conferred transcriptional memory by facilitating the binding of the transcriptional regulator STAT6 and RNA polymerase II, leading to robust production of enhancer and mRNAs upon IL-4 re-stimulation. Ligand-insensitive PPARγ binding controlled the expression of an extracellular matrix remodeling-related gene network in macrophages. Expression of these genes increased during muscle regeneration in a mouse model of injury, and this increase coincided with the detection of IL-4 and PPARγ in the affected tissue. Thus, a predominantly ligand-insensitive PPARγ:RXR cistrome regulates progressive and/or reinforcing macrophage polarization.
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IFN-γ, IL-4, Nuclear receptor, PPARγ, coregulators, epigenomics, ligand-insensitive enhancers, macrophage polarization, muscle regeneration, progressive polarization, transcriptional memory, Animals, Cell Line, Cells, Cultured, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Interleukin-4, Ligands, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Knockout, PPAR gamma