High-Resolution Mapping and Dynamics of the Transcriptome, Transcription Factors, and Transcription Co-Factor Networks in Classically and Alternatively Activated Macrophages

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.

<p>Functional aspects, phenotypic heterogeneity, and tissue immune response of macrophages in infectious diseases</p>

“…With advances in technology, discovery of the transcriptome has allowed for identification of several genes related to the phenotypic modulation of macrophages. 71,72 This transcriptomic characterization of the phenotypes M1, M2, and M4 is a topic that needs to be addressed. 73,74 For instance, the integrated network established by a combination of factors typically characterizes a complex phenomenon where real-time polymerase chain reaction (PCR) validation, for example, shows that the expression of CD38, Gpr18, and Fpr2 is exclusive to the M1 phenotype.…”

MiR-202-5p Promotes M2 Polarization in Allergic Rhinitis by Targeting MATN2

“…Not only might intracellular kinases and transcription factors control the activation and polarization of macrophages [8, 9], but also microRNAs (miRNAs) emerge as critical regulators to rewire functional phenotypes of macrophages [10-12], which could be utilized as biomarkers or therapeutic targets against diverse immunologic and inflammatory diseases. While little miRNA research has been done in AR, the aim of this investigation is to determine the role of miR-202-5p in AR.…”

Transcriptionally induced enhancers in the macrophage immune response toMycobacterium tuberculosisinfection

“…BMDM are not dependent on health condition of the donor mice, and this choice enabled us to obtain high numbers of cells required for the CAGE analysis. These advantages have also been appealing to other researchers, and BMDM have been used as the primary macrophage model in many immunological transcriptomic studies [79][80][81]. One of the crucial areas of TB research is the development of novel strategies for host-directed therapies, which can stimulate host antimicrobial pathways and suppress host subversion by M.tb [82,83].…”