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The multifaceted responses of human monocytes to IFN-gamma and IL-4 are not reducible to M1/M2 polarization of Macrophages

ABSTRACT: Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36537 | GEO | 2013/03/15

SECONDARY ACCESSION(S): PRJNA153409

REPOSITORIES: GEO

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The multifaceted responses of human monocytes to IFN-gamma and IL-4 are not reducible to M1/M2 polarization of Macrophages

Project description:Macrophages are known to be polarized into inflammatory (M1) and immunoregulatory (M2) cells when they are stimulated by agonists such as IFN-gamma and IL-4, respectively. If circulating monocytes may be polarized in response to T cell signals is often misguidedly deduced from macrophage results. Here the transcriptional responses of human CD14+ monocytes to IFN-gamma and IL-4 were analyzed using whole genome microarrays. A principal component analysis and hierarchical clustering showed that monocyte and macrophage responses were distinct. Monocytes stimulated with IFN-gamma and IL-4 for 6 hours exhibited some features of macrophage polarization. Indeed, when 80 genes considered as M1 and M2 genes were analyzed, we found that M1 genes were modulated in response to IFN-gamma and that M2 genes were modulated in response to IL-4. The M1 polarization of monocytes was transient because only M2 genes were modulated when monocytes were stimulated with IFN-gamma and IL-4 for 18 hours. However, the activation of monocytes by IFN-gamma and IL-4 could not be reduced to M1/M2 polarization status. Indeed, monocytes exhibited early specific signatures composed of 46 and 39 up-regulated genes in response to IFN-gamma and IL-4, respectively, and a late signature common to both molecules that consisted of 57 up-regulated genes. Taken together, these results demonstrated the extreme plasticity of human monocytes and suggested the existence of a core transcriptional termination program. Using early and late signatures might be pertinent to investigate monocyte activation in inflammatory or infectious diseases. Monocytes were stimulated with IFN-gamma (20ng/mL) or IL-4 (20ng/mL) for 6 and 18 hours or culture for 6 and 18 hours without agonist (Unstimulated samples). Monocytes-derived-macrophages (MDM) stimulated with IFN-gamma and IL-4 for 18 hours were used as controls. Each microarray is derived from a single biological sample.

2013-03-15 | E-GEOD-36537 | biostudies-arrayexpress

The Paradigm of Macrophage Polarization is not Applicable per seto Human Circulating Monocytes

Project description:Macrophage activation is required for the control of innate and adaptive immune responses. The classification in M1 and M2 macrophages based on a combination of small numbers of membrane and soluble markers is operational in murine and human macrophages. If this classification may be extended to circulating monocytes is not elucidated. To answer such question, human monocytes were stimulated for 6 and 18 hours with IFN-gamma and IL-4, two canonical agonists of M1/M2 polarization in macrophages, and gene expression programs were investigated with whole genome microarrays. The temporal analysis of these programs showed marked differences to both IFN-gamma and IL-4. In 6-h stimulated monocytes, gene categories related to inflammatory and immune responses were enriched, and these monocytes exhibited a M1 and M2 polarization in response to IFN-gamma and IL-4, respectively, as found in macrophages. In 18-h stimulated monocytes, the categories related to innate immunity and metabolic pathways were enriched in response to IFN-gamma and IL-4, whereas PPAR signaling pathway was specifically enriched in response to IL-4. In addition, the M1 and M2 polarization induced by IFN-gamma and IL-4, respectively, was replaced by an original transcriptional program that did not depend on IFN-gamma and IL-4. This program appeared as networks around chemokines, NF-kappaB/MAP kinase pathways and MHC class II molecules. These results clearly demonstrated that monocyte activation consisted of an early polarized stage likely involved in effector responses and a delayed stage that may regulate host responses. The establishment of databases on human circulating monocytes using high throughput methods may be critical for pathophysiological and clinical non-invasive studies. Peripheral blood mononuclear cells (PBMCs) were isolated from leukopacks from normal blood donor buffy coats (Etablissement FranÃ§ais du Sang, Marseille, France) by Ficoll density gradient

2012-12-07 | E-GEOD-27658 | biostudies-arrayexpress

Expression data from macrophage maturation and polarization c-Myc in alternative macrophage activation experiments

Project description:In response to microenvironmental signals macrophages undergo different activation, indicated as classic/M1 and alternative/M2 polarization. C-Myc transcription factor could be an essential player in M2 polarization. Functional relevance of c-Myc in M2 macrophage biology is investigated by evaluating the effect of 100-58F4, on the transcriptional profile induced on human macrophages by IL-4. Human monocytes were obtained from normal donor buffy coats by two-step gradient centrifugation using Ficoll (Biochrom) and Percoll (Amersham). Non-adherent cells were discarded, and the purified monocytes were incubated for 7 days in RPMI 1640 (Biochom) supplemented with 10% FCS (HyClone) and 100 ng/mL M-CSF to obtain resting macrophages. Macrophage polarization was obtained by removing the culture medium and culturing cells in RPMI 1640 supplemented with 10% FCS and 100 ng/mL LPS plus 20 ng/mL IFN-gamma (M1 polarization) or 20 ng/mL IL-4 (M2 polarization) for 24 h. When needed, chemical inhibitors were added with IL-4.

2011-09-15 | E-GEOD-32164 | biostudies-arrayexpress

FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor associated macrophages

Project description:Bone marrow derived macrophages from C57BL/6 mice were stimulated into M1 and M2 polarization state. Analysis of BMDMs from LysMcre;FoxO1Fl/FL mice and control littermates. Results provide insight into the regulatory role of FoxO1 during macrophage polarization. BMDMs were stimulated with 100ng/ml LPS plus 20ng/ml IFN-γ into M1 polarization, and stimulated with 10ng/ml IL-4 plus 10ng/ml IL-13 into M2 polarization. Both for 24 hours. Unstimulated cells as M0 state.

2018-09-01 | GSE97260 | GEO

IFN-γ and IL-4 regulate epigenetic modifiers in macrophages

Project description:Interferon-γ (IFN-γ) or interleukin-4 (IL-4) prime macrophages towards classical (M1) or alternative (M2) activation, respectively. How IFN-γ and IL-4 prime epigenetic responses by altering expression of histone modifying enzymes and how this affects M1/M2 polarization is incompletely understood.

2017-01-15 | GSE83957 | GEO

Beta-adrenergic-activated macrophages: Location in the M1-M2 spectrum and transcriptional regulation

Project description:Genome-wide transcriptional profiling results were used to systematically assess the extent to which transcriptomes of beta-adrenergic-activated macrophages show expression of genes that are characteristic of the canonical IL-4-stimulated M2 macrophage vs. IFN-gamma-stimulated M1 macrophage and to infer potential transcriptional regulators.

2016-10-11 | GSE80185 | GEO

Development, phenotype and function of a distinct macrophage subpopulation induced by IL-23

Project description:Macrophages acquire distinct phenotypes during tissue stress and inflammatory responses. Classically, macrophages are categorized into two different subsets named inflammatory M1 and anti-inflammatory M2 macrophages. We herein identified a unique pathogenic macrophage subpopulation, named M17, driven by IL-23 with a distinct gene expression profile including cytokines and membrane molecules. In contrast to M1 and M2-polarized macrophages, M17 macrophages express high levels of CXCR5 on the cell surface and produce large amounts of IL-17A, IL-22 and IFN-γ. IL-23 induces IL-17A expression in macrophages through the signal transducer and activator of transcription 3 (STAT3)-retinoid related orphan receptor-γ T (RORγT) pathway, while induces IFN-γ through T-bet. Importantly, IL-23-induced M17 macrophage polarization promotes the pathogenesis of psoriasis in vivo. The characteristics and significances of M17 macrophage subpopulation in the physiological status and pathogenesis caused by infections, tumors and graft rejection needs to be explored.

2018-03-12 | GSE102274 | GEO

CCR-5 using HIV-1 induces an anti-inflammatory profile in primary macrophages

Project description:Macrophages are important effector cells of the immune system and play an important role in mounting inflammatory responses. Macrophages can be activated by different stimuli in the tissue, either by cytokines produced by T helper cells (M1 or M2 polarization) or by the pathogens they encounter. Macrophages are also important target cells of HIV-1 and are preferentially infected by CCR5-using viruses. In this study, we investigated the ability of HIV-1 to induce changes in gene expression in unpolarized macrophages as well as in M1 or M2 polarized cells. We observed that CCR5-using HIV-1 regulates the expression of genes that are also regulated by IL-4 in macrophages. Genes regulated by HIV-1 infection and IL-4 polarization are involved in dampening pro-inflammatory responses in macrophages, which may facilitate HIV-1 to escape from detection by other immune cells. We also observed that changes in macrophage gene expression triggered by CCR5-using HIV-1 differed from those regulated by a CXCR4-using virus. This indicates that CCR5-using HIV-1 may be able to modulate macrophage gene expression to achieve successful replication. Our results provide insight in the complex interplay between HIV-1 and cells of the immune system. Polarized macrophages were obtained by stimulation of primary human monocytes with IFN-gamma (250 U/ml) in combination with TNF-alpha (12.5 ng/ml) (M1), IL-4 (50 ng/ml) (M2a), IL-10 (50 ng/ml) (M2c) for 5 days. Cells were inoculated for 24 hours with one of two HIV-1 strains (CCR5 or CXCR4 using HIV1) or their non replicating counterparts (heat inactivated virus). Macrophages that were not stimulated wiht cyokines or inoculates with HIV-1 were used as control. A total of 16 treatment conditions were tested in triplicate, for a total of 48 samples analysed.

2015-08-01 | E-GEOD-55029 | biostudies-arrayexpress

Expression data from M(LPS+IFNγ) and M(IL4)

Project description:Human monocyte THP-1 cells obtained from ATCC were cultured in RPMI 1640 (Invitrogen, Carlsbad, CA) containing 10% FBS and supplemented with 10 mM Hepes (Gibco BRL). THP-1 was differentiated into macrophages by 24-h incubation with 160 nM phorbol 12-myristate 13-acetate (PMA; Sigma, St. Louis, MO) followed by 24-h incubation in RPMI medium. Macrophages were further polarized to M1 macrophages by incubation with 10 pg/ml of lipopolysaccharide (LPS; Sigma) and 20 ng/ml of interferon (IFN)-γ (R&D Systems, MN) and are referred to as M(LPS+IFN-γ) cells. M2 macrophages were obtained by incubation with 20 ng/ml of interleukin (IL)-4 (R&D Systems) and are referred to as M(IL4) cells. To test the represented polarization marker of PMA differentiated-THP-1 macrophages stimulated with 20 ng ml(-1) IFNγ + 10 pg ml(-1) LPS and 20 ng ml(-1) IL-4, which are known to influence macrophage polarization in vetro into the M1 and M2 state, respectively. We used microarrays to detail the gene expression pools to identify distinct M1 and M2 state during this process.

2017-02-28 | GSE95405 | GEO

Genome-wide analysis of M1 and M2 polarized macrophages with CNI-1493 treatment

Project description:Analysis of the effects of CNI-1493 treatment on M1 and M2 polarized macrophages. The purpose of this microarray is to identify genes that may be differentially expressed in M1 or M2 macrophages after treatment with CNI-1493. CNI-1493 is a known inhibitor of M1 macrophages but details of its molecular mechanism are unknown. The effect of CNI-1493 on M2 macrophages has yet to be explored, but we hypothesize that CNI-1493 treatment will attenuate pro-tumor properties of M2 macrophages. We demonstrate with this array that known macrophage markers are unchanged after treatment with CNI-1493, indicating that CNI-1493 does not change the macrophage phenotype on a transcriptional level. Additionally, no candidate genes to suggest how CNI-1493 may attenuate the pro-tumor effects of M2 macrophages are readily identifiable. Total RNA extracted from M1 or M2 macrophages after polarization with GM-CSF (25ng/ml) or M-CSF (25ng/ml) for 7 days, followed by addition of IFN-γ (20ng/ml) and LPS (100ng/ml) or IL-4 (40ng/ml) for 18 hours, respectively, from CD14+ human PBMCs, and treated with CNI-1493 (200nM)

2015-03-12 | E-GEOD-66805 | biostudies-arrayexpress

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