Abstract
Macrophages are the prime innate immune cells of the inflammatory response, and the combination of multiple signaling inputs derived from the recognition of host factors [e.g., interferon-g (IFN-γ)] and invading pathogen products (e.g., toll-like receptors (TLRs) agonists) are required to maintain essential macrophage function. The profound effects on biological outcomes of inflammation associated with IFN-γ pretreatment (“priming”) and TLR4 ligand bacterial lipopolysaccharide (LPS)-induced macrophage activation (M1 or classical activation) have long been recognized, but the underlying mechanisms are not well defined. Therefore, we analyzed gene expression profiles of macrophages and identified genes, transcription factors (TFs), and transcription co-factors (TcoFs) that are uniquely or highly expressed in IFN-γ-mediated TLR4 ligand LPS-inducible versus only TLR4 ligand LPS-inducible primary macrophages. This macrophage gene expression has not been observed in macrophage cell lines. We also showed that interleukin (IL)-4 and IL-13 (M2 or alternative activation) elicited the induction of a distinct subset of genes related to M2 macrophage polarization. Importantly, this macrophage gene expression was also associated with promoter conservation. In particular, our approach revealed novel roles for the TFs and TcoFs in response to inflammation. We believe that the systematic approach presented herein is an important framework to better understand the transcriptional machinery of different macrophage subtypes.
Highlights
Macrophages are major innate immune cell populations that respond to a microbial insult or danger signal, are specialized for phagocytosis, and play a central role in the immune response [1, 2]
Using a false discovery rate (FDR ≤ 0.01), P ≤ 0.01 and log2-fold change ≥1.5 as the cutoff values for the up or downregulation of genes, we identified genes that were altered in LPS-stimulated bone marrow-derived macrophages (BMDMs): 596 genes at 1 h and 2,248 genes at 4 h were differentially expressed
RNA-seq approaches identified among multiple regulators of epigenetic families, only histone methyltransferases (SETDB2), histone demethylases (KDM4A), and histone deacetylases (HDAC1) were significantly differentially expressed (Figure 1B). These findings suggest that SETDB2, KDM4A, and HDAC1 have an important role in the regulation of BMDM activation
Summary
Macrophages are major innate immune cell populations that respond to a microbial insult or danger signal, are specialized for phagocytosis, and play a central role in the immune response [1, 2]. Most tissue-resident macrophages arise from embryonic origin and have the capacity to self-renewing adult bone marrow-derived macrophages (BMDMs) [2, 3] STAT1 targeted interferon regulatory factor-1 (IRF1) has been shown to contribute to a multi-layer integration of IFN-γ signaling [14]. These downstream signal transduction cascade and their molecules have been discovered in macrophages, the molecular mechanisms of the IFN-γ-mediated TLR4 crossregulation in murine macrophages remain largely unaddressed and are under active investigation
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