TLR-dependent transcriptional reprogramming of LXRa cistrome in bone marrow-derived macrophages

The Liver X receptors (LXRa and LXRß) are members of the nuclear receptor superfamily of transcription factors, and play key roles in the coordination of both metabolic and immune responses in macrophages. Both LXRs are expressed in macrophages and they share a high degree of sequence homology but their individual roles in different models of macrophage cultures, particularly in response to inflammation, have not been characterized. Previous studies have shown that ligand pre-treated LXRs repress the induction of pro-inflammatory cytokines in macrophages. Here, we show evidence that the expression of LXRa (but not LXRß) is transcriptionally regulated at late phases of an LPS-induced inflammatory response in bone marrow-derived macrophages (BMDMs). Regulation of LXRa expression is controlled at the transcriptional levels by inflammatory signaling networks. Transcriptional profiling studies and ChIP-seq data identified a number of innate immune pathways whose expression is substantially controlled by LXRa in BMDMs. In summary, our data shows that LXRa plays a previously unrecognized role in innate immunity by transcriptional regulation of a battery of inflammatory genes through TLR and Type-I IFN-dependent signaling in macrophages. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for nuclear receptor LXR-alpha, p65 subunit of transcription factor NF-kB, and the histone modification H3K27ac in BMDM cells.