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Suppression of LPS-induced IFNg and NO in splenocytes by select E2-regulated miRNA: A novel mechanism of immune mod.

ABSTRACT: microRNA (miRNA), recently identified, non-coding, small RNA, are emerging as key regulators in homeostasis of the immune system. Therefore, aberrant expression of miRNA may be linked to immune dysfunction, such as in chronic inflammation and autoimmunity. In this study, we investigated the potential role of miRNA in estrogen-mediated regulation of innate immune responses, as indicated by upregulation of LPS-induced IFNg, inducible nitric oxide synthase (iNOS), and nitric oxide in splenic lymphocytes from estrogen-treated mice. We found that miR-146a, a negative regulator of Toll-like receptor (TLR) signaling, was decreased in freshly-isolated splenic lymphocytes from estrogen-treated mice compared to placebo controls. Increasing the activity of miR-146a significantly inhibited LPS-induced IFNg and iNOS expression in mouse splenic lymphocytes. Further, miRNA microarray and Real-time RT-PCR analysis revealed that estrogen selectively upregulates/downregulates the expression of miRNA in mouse splenic lymphocytes. miR-223, which is highly upregulated by estrogen, regulates LPS-induced IFNg, but not iNOS or nitric oxide in splenic lymphocytes. Inhibition of miR-223 activity decreased LPS-induced IFNg in splenic lymphocytes from estrogen-treated mice. Our data are the first demonstrating selective regulation of miRNA expression in immune cells by estrogen and are indicative of an important role of miRNA in estrogen-mediated immune regulation. Keywords: microRNAs, estrogen, splenic lymphocytes, TLR4 signaling, mouse

ORGANISM(S): Mus musculus

PROVIDER: GSE11197 | GEO | 2008/12/05

SECONDARY ACCESSION(S): PRJNA106791

REPOSITORIES: GEO

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Suppression of LPS-induced IFNg and NO in splenocytes by select E2-regulated miRNA: A novel mechanism of immune mod.

Project description:microRNA (miRNA), recently identified, non-coding, small RNA, are emerging as key regulators in homeostasis of the immune system. Therefore, aberrant expression of miRNA may be linked to immune dysfunction, such as in chronic inflammation and autoimmunity. In this study, we investigated the potential role of miRNA in estrogen-mediated regulation of innate immune responses, as indicated by upregulation of LPS-induced IFNg, inducible nitric oxide synthase (iNOS), and nitric oxide in splenic lymphocytes from estrogen-treated mice. We found that miR-146a, a negative regulator of Toll-like receptor (TLR) signaling, was decreased in freshly-isolated splenic lymphocytes from estrogen-treated mice compared to placebo controls. Increasing the activity of miR-146a significantly inhibited LPS-induced IFNg and iNOS expression in mouse splenic lymphocytes. Further, miRNA microarray and Real-time RT-PCR analysis revealed that estrogen selectively upregulates/downregulates the expression of miRNA in mouse splenic lymphocytes. miR-223, which is highly upregulated by estrogen, regulates LPS-induced IFNg, but not iNOS or nitric oxide in splenic lymphocytes. Inhibition of miR-223 activity decreased LPS-induced IFNg in splenic lymphocytes from estrogen-treated mice. Our data are the first demonstrating selective regulation of miRNA expression in immune cells by estrogen and are indicative of an important role of miRNA in estrogen-mediated immune regulation. Keywords: microRNAs, estrogen, splenic lymphocytes, TLR4 signaling, mouse Total RNAs were isolated from freshly-isolated splenic lymphocytes from 2 pairs of placebo-and estrogen-treated mice

2008-12-04 | E-GEOD-11197 | biostudies-arrayexpress

T cell cancer therapy requires CD40-CD40L activation of TNFα-iNOS-producing dendritic cells

Project description:The effectiveness of new cancer therapies such as checkpoint blockade and adoptive cell transfer of activated anti-tumor T cells requires overcoming immunosuppressive tumor microenvironments. We found that the activation of tumor-infiltrating myeloid cells to produce local nitric oxide is a prerequisite for adoptively transferred CD8+ cytotoxic T cells to destroy tumors. These myeloid cells are phenotypically similar to ‘Tip-DCs’ or nitric oxide- and TNFα-producing dendritic cells. The nitric oxide-dependent killing was tempered by coincident arginase 1 expression, which competes with iNOS for arginine, the substrate for nitric oxide production. Depletion of immunosuppressive CSF-1R-dependent arginase 1+ myeloid cells enhanced nitric oxide-dependent tumor killing. Tumor killing via iNOS was independent of the microbiota but dependent on the CD40-CD40L pathway and, in part, lymphotoxin alpha. We extended our findings in mice to uncover a strong correlation between iNOS, CD40 and TNF expression and survival in colorectal cancer patients. Our results identify a network of anti-tumor targets to boost the efficacy of cancer immunotherapies.

2016-09-14 | GSE74427 | GEO

Polymicrobial sepsis-induced Myocardial Depression Transcriptional Profile

Project description:To describe the transcriptional changes associated with polymicrobial-sepsis induced myocardial depression in wild type and iNOS deficient mice. Keywords: myocardium, contractility, differential gene expression, nitric oxide synthase, infection

2010-11-17 | GSE9667 | GEO

Emodin inhibits macrophage classical activation [Control-LPS-IFNg-Emodin]

Project description:In order to fully characterize emodin's effects on macrophage activation, peritoneal macrophages were stimulated with LPS+IFNg with or without emodin and gene expression was analyzed using a whole genome microarray. Emodin significantly attenuated the IFNg/LPS induced changes in a large percentage of responsive genes (31%) through inhibiting multiple signaling pathways. RT-qPCR was used to confirm the results in several genes associated with M1 macrophage activation including: TNF, IL6, IL1b, iNOS, MMP2, and MMP9. Three-condition, one-color experiment: Vehicle control, LPS-IFNg or LPS-IFNg-Emodin treated periferal WBC PMN samples: 4 biological replicates each.

2016-07-04 | E-GEOD-73310 | biostudies-arrayexpress

The role of Gch1 and Nos2 in the macrophage response to BCG infection

Project description:Inducible nitric oxide synthase (iNOS) plays a crucial role in controlling growth of mycobacteria, presumed to be via nitric oxide (NO) mediated killing. However, NOS enzymes can also signal through NO-independent pathways, and production of NO by NOS requires the cofactor tetrahydrobiopterin (BH4). We compared Nos2-/- mice to mice with macrophage BH4 deficiency (Gch1fl/flTie2cre), due to a leukocyte-specific deletion of Gch1, to uncover the specific contribution of NO-independent NOS functions to anti-mycobacterial immunity. We used microarrays to detail the global programme of gene expression in uninfected and BCG infected macrophages that were either deficient in iNOS (Nos2-/- vs C57bl6/J) or BH4/Gch1 (GCHfl/flTie2cre vs GCHfl/fl)

2018-11-30 | GSE107543 | GEO

MiR expression profile in M1-polarized bone marrow derived macrophage cells compared with normal mouse aortic tissue.

Project description:The global change of the miR expression profile during atherosclerosis is due to the infiltration of different types of leukocytes into the arterail vessel wall in addition to disease-specific regulation in vascular cells. Monocyte-derived macrophage accumulation in the subintimal region is critical in the formation of atherosclerotic plaques. It is currently unknown which miRs are involved in the atherogenic macrophage response. The comparison of the miR expression profile in LPS/Interferon-gamma activated mouse macrophages with the miR expression in the normal aortic vessel wall was performed to detect macrophage-enriched miRs. This screening may help to identify macrophage-enriched miRs in atherosclerotic vessels that may play a role in the macrophage function during atherogenesis. Bone marrow cells were harvested from femura of 6-8 week old female C57BL/6 mice, re-suspended in DMEM-F12/10% FCS/10% L929-conditioned medium, and cultured for 7 days to differentiate into primary macrophages. F4/80 and CD11b expression was determined by flow cytometry to confirm the macrophage phenotype. Macrophages were stimulated with LPS (100ng/ml, 14 hours) and INF-g (10ng/ml, 6 hours) and the M1 polarization was verified by quantification of mannose receptor C type 1 (MRC1), arginase II (ArgII), inducible nitric oxide synthase (iNOS), and arginase I (ArgI) by qRT-PCR. Total RNA (M1-type macrophages and aorta tissue) was isolated using mirVana microRNA Isolation Kit.

2014-01-01 | E-GEOD-26556 | biostudies-arrayexpress

IFNγ sensitizes macrophages to pathogen ligand killing via a unique caspase-8 and mitochondrial cell death pathway licensed by nitric oxide

Project description:Caspase-8 modulates TLR-induced gene transcription, which is only partially dependent on caspase-8 catalytic activity. Moreover, The slow kinetics of IFNγ and LPS-induced BMDM killing offers the possibility that transcriptional responses may contribute to cell death activation. We performed 3' mRNA-sequencing to examine whether caspase-8 might contribute, at least in part, to IFNγ and LPS-triggered macrophage death via its transcriptional role. We found that caspase-8-mediated transcriptional re-programming of BMDMs. Importantly, caspase-8 modulates expression of Bcl-2 family members and inducible nitric oxide synthase (iNOS) to promote activation of the mitochondrial apoptotic effectors, BAX and BAK.

2021-12-15 | GSE161179 | GEO

MiR expression profiles in M1-polarized compared with unstimulated (MÐ¤) bone marrow-derived macrophage cells

Project description:The global change of the miR expression profile during atherosclerosis is due to the infiltration of different types of leukocytes into the arterial vessel wall in addition to disease-specific regulation in vascular cells. Monocyte-derived macrophage accumulation in the subintimal region is critical in the formation of atherosclerotic plaques. It is currently unknown which miRs are involved in the atherogenic macrophage response. The comparison of the miR expression profile in LPS/Interferon-gamma activated mouse macrophages with the miR expression in the unstimulated mouse macrophages was performed to detect M1-type macrophage-enriched miRs. This screening combined with our miR profiling in atherosclerotic vessels may help to identify M1-type macrophage-enriched miRs in atherosclerotic vessels that may play a role in the macrophage function during atherogenesis. Bone marrow cells were harvested from femura of 6- to 8-week-old female C57BL/6 mice, re-suspended in DMEM-F12/10% FCS/10% L929-conditioned medium, and cultured for 7 days to differentiate into primary macrophages. F4/80 and CD11b expression was determined by flow cytometry to confirm the macrophage phenotype. Macrophages were stimulated with LPS (100ng/ml, 14 hours) and INF-g (10ng/ml, 6 hours), and the M1 polarization was verified by quantification of mannose receptor C type 1 (MRC1), arginase II (ArgII), inducible nitric oxide synthase (iNOS), and arginase I (ArgI) by qRT-PCR. Total RNA (M1-type and unstimulated (MÐ¤) macrophages) was isolated using the mirVana microRNA Isolation Kit.

2012-12-26 | E-GEOD-33453 | biostudies-arrayexpress

Nitric oxide modulates metabolic remodelling and immunometabolism in inflammatory murine macrophages

Project description:Classical stimulation of macrophages (MLPS/IFNγ) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of nitric oxide (NO) and inhibiting respiration. Consequent upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. Here we show that the NOS cofactor tetrahydrobiopterin (BH4) modulates key aspects of metabolic remodelling in activated bone-marrow-derived macrophages (BMDMs) via NO production. Using two complementary mouse models that each lack the capacity for inducible NO generation, through different mechanisms, we reveal that NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I, by HIF1α-mediated glycolytic remodelling, and by modulating levels of the critical TCA cycle metabolites, and inflammatory mediators, citrate, succinate, and itaconate. Taken together, our findings reveal new critical roles for iNOS-derived NO that are required for metabolic remodelling and cytokine production in macrophage inflammatory responses.

2019-05-31 | PXD010628 | Pride

Comparing RNA expression profiles of KALori and KANSL mouse lungs

Project description:We have reported that pulmonary infiltrating macrophages, which highly express inducible nitric-oxide synthase (iNOS/NOS2), play a critical role for driving spontaneous lung SCC development in a new mouse model (L-Ikka KA/KA; KA/KA) that mimics human lung SCC development. However, the role of NOS2 in lung SCC development is unknown. Our data suggests deletion of the gene iNOS prevents tumorogenesis in this mouse model. We use microarray data to compare levels of expression of genes associated with lung tumor development and prevention.

2017-07-22 | GSE101759 | GEO

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