The IL-4/STAT6/PPARγ signaling axis is driving the expansion of the RXR heterodimer cistrome, providing complex ligand responsiveness in macrophages

Abstract

Retinoid X receptor (RXR) is an obligate heterodimeric partner of several nuclear receptors (NRs), and as such a central component of NR signaling regulating the immune and metabolic phenotype of macrophages. Importantly, the binding motifs of RXR heterodimers are enriched in the tissue-selective open chromatin regions of resident macrophages, suggesting roles in subtype specification. Recent genome-wide studies revealed that RXR binds to thousands of sites in the genome, but the mechanistic details how the cistrome is established and serves ligand-induced transcriptional activity remained elusive. Here we show that IL-4-mediated macrophage plasticity results in a greatly extended RXR cistrome via both direct and indirect actions of the transcription factor STAT6. Activation of STAT6 leads to chromatin remodeling and RXR recruitment to de novo enhancers. In addition, STAT6 triggers a secondary transcription factor wave, including PPARγ. PPARγ appears to be indispensable for the development of RXR-bound de novo enhancers, whose activities can be modulated by the ligands of the PPARγ:RXR heterodimer conferring ligand selective cellular responses. Collectively, these data reveal the mechanisms leading to the dynamic extension of the RXR cistrome and identify the lipid-sensing enhancer sets responsible for the appearance of ligand-preferred gene signatures in alternatively polarized macrophages.

Inflamed synovial fluid induces a homeostatic response in bone marrow mononuclear cells in vitro: Implications for joint therapy

“…[94][95][96] IL-6 is required to induce expression of the IL-4 receptor and consequently the IL-4 signaling pathway leading to homeostatic functions in macrophages. [94][95][96][97][98] Gene expression for IL-4r was upregulated both in SF and ISF cultures in our study, but was almost 2-fold higher in ISF compared to SF. Increased IL-6, along with increased gene expression for IL-4r, and the overall findings of our study, agree with a previous report of IL-6 driving macrophages toward a homeostatic phenotype.…”

“…IL‐6 deficiency induces M1‐like macrophage polarization and inflammatory diseases . IL‐6 is required to induce expression of the IL‐4 receptor and consequently the IL‐4 signaling pathway leading to homeostatic functions in macrophages . Gene expression for IL‐4r was upregulated both in SF and ISF cultures in our study, but was almost 2‐fold higher in ISF compared to SF.…”

Notch signaling increases PPARγ protein stability and enhances lipid uptake through AKT in IL‐4‐stimulated THP‐1 and primary human macrophages

“…IL‐4/IL‐4R signaling activates STAT6 and AKT1, leading to a second wave of the activation of transcription factors, such as PPARγ, a key transcription factor of M(IL‐4) [7–10]. M(IL‐4) upregulates a set of genes involved in anti‐inflammation, lipid metabolism, apoptotic cell clearance, and cellular metabolism [1,11–13].…”

Unraveling the Hierarchy of cis and trans Factors That Determine the DNA Binding by Peroxisome Proliferator-Activated Receptor γ

“…However, its cistrome is very dynamic, and its expression largely increases during alternative macrophage polarization upon interleukin-4 (IL-4) stimulation in both human and mouse models (17,22,23). IL-4 treatment of mouse bone marrow-derived macrophages (BMDMs) results in a significant extension of the PPAR␥/RXR cistrome, which is coupled with the commissioning of thousands of previously unoccupied binding sites (17,24). Although more than half of the PPAR␥/RXR cistrome shows some activity, e.g., enhancer transcription, only a small fraction of these sites shows responsiveness to the synthetic PPAR␥ ligand rosiglitazone (RSG).…”