IL-10 inhibition of miR-155 in inflammation
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ABSTRACT:
PROVIDER: PRJNA637382 | ENA |
REPOSITORIES: ENA
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Project description:Inflammatory disorders including arthritis, inflammatory bowel disease, psoriasis and multiple sclerosis are characterised by the excessive production of pro-inflammatory cytokines resulting in inflammation, tissue damage and chronic pain. In a healthy immune system, the host has developed mechanisms to protect itself from excessive inflammation. One such mechanism is mediated by the anti-inflammatory cytokine IL-10, which primarily acts to limit the production of pro-inflammatory cytokines and antigen presenting capabilities of cells in the innate immune system. Since the discovery of IL-10, much emphasis has been placed on extrapolating its exact mechanism of inhibition with the aim of potentiating its use therapeutically. Significantly, the systemic administration of IL-10 has had success in many animal models of inflammation as well as clinical success in human disorders such as psoriasis and Crohn’s disease. Despite this, major gaps in our knowledge remain which have weakened the expected therapeutic effect for this anti-inflammatory cytokine. Our early studies discovered that in response to innate immune stimulation, IL-10 can potently inhibit miR-155 (McCoy et al., 2010), a miRNA characterised as a promoter of inflammation and found over-expressed in autoimmune pathologies. This finding suggests that the IL-10/miR-155 axis is a novel mechanism utilised by IL-10 to administer its function. In this study, an Affymetrix array was employed to characterise genes regulated by the IL-10/miR-155 axis in bone-marrow derived macrophages. This project proposal aims to characterise the mechanism of IL-10 inhibition on miR-155, as well as understand the functional outcome and significance of this effect by characterising genes regulated by the IL-10/miR-155 axis.
2020-11-30 | GSE151835 | GEO
Project description:Classically activated (M1) macrophages protect from infection but can cause inflammatory disease and tissue damage while alternatively activated (M2) macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. The inflammation-associated miRNA, miR-155, was rapidly up-regulated over 100-fold in M1, but not M2, macrophages. Inflammatory M1 genes and proteins iNOS, IL-1b and TNF-a were reduced up to 72% in miR-155 knockout mouse macrophages, but miR-155 deficiency did not affect expression of genes associated with M2 macrophages (e.g., Arginase-1). Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed iNOS and TNF-a gene expression in wild-type M1 macrophages. Comparative transcriptional profiling of unactivated (M0) and M1 macrophages derived from wild-type and miR-155 knockout (KO) mice revealed an M1 signature of approximately 1300 genes, half of which were dependent on miR-155. Real-Time PCR of independent datasets validated miR-155's contribution to induction of iNOS, IL-1b, TNF-a, IL-6 and IL-12, as well as suppression of miR-155 targets Inpp5d, Tspan14, Ptprj and Mafb. Overall, these data indicate that miR-155 plays an essential role in driving the differentiation and effector potential of inflammatory M1 macrophages. Total RNA was prepared from bone marrow-derived macrophages of miR-155 knockout mice (n=2 independent mice) treated in M0, M1 or M2 conditions (n=2 replicates per condition originating from different mice)
2016-07-15 | E-GEOD-77425 | biostudies-arrayexpress
Project description:Classically activated (M1) macrophages protect from infection but can cause inflammatory disease and tissue damage while alternatively activated (M2) macrophages reduce inflammation and promote tissue repair. Modulation of macrophage phenotype may be therapeutically beneficial and requires further understanding of the molecular programs that control macrophage differentiation. A potential mechanism by which macrophages differentiate may be through microRNA (miRNA), which bind to messenger RNA and post-transcriptionally modify gene expression, cell phenotype and function. The inflammation-associated miRNA, miR-155, was rapidly up-regulated over 100-fold in M1, but not M2, macrophages. Inflammatory M1 genes and proteins iNOS, IL-1b and TNF-a were reduced up to 72% in miR-155 knockout mouse macrophages, but miR-155 deficiency did not affect expression of genes associated with M2 macrophages (e.g., Arginase-1). Additionally, a miR-155 oligonucleotide inhibitor efficiently suppressed iNOS and TNF-a gene expression in wild-type M1 macrophages. Comparative transcriptional profiling of unactivated (M0) and M1 macrophages derived from wild-type and miR-155 knockout (KO) mice revealed an M1 signature of approximately 1300 genes, half of which were dependent on miR-155. Real-Time PCR of independent datasets validated miR-155's contribution to induction of iNOS, IL-1b, TNF-a, IL-6 and IL-12, as well as suppression of miR-155 targets Inpp5d, Tspan14, Ptprj and Mafb. Overall, these data indicate that miR-155 plays an essential role in driving the differentiation and effector potential of inflammatory M1 macrophages.
2016-07-15 | GSE77425 | GEO
Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals. PARALLEL study design with 26 samples. Biological replicates: 2 to 3 replicates per group with wild type air exposed animals as controls for each time point (24, 48, 72 hours). Time-Course, Dose-Response, Strain comparison
2011-10-18 | E-GEOD-25095 | biostudies-arrayexpress
Project description:Background: The mechanisms underlying ozone (O3)-induced pulmonary inflammation remain unclear. Interleukin (IL)-10 is an anti-inflammatory cytokine that is known to inhibit inflammatory mediators. Objectives: The current study investigated the molecular mechanisms underlying IL-10-mediated attenuation of O3-induced pulmonary inflammation in mice. Methods: Il10-deficient (Il10-/-) and wild type (Il10+/+) mice were exposed to 0.3-ppm O3 or filtered air for 24, 48 or 72 hr. Immediately following exposure, differential cell counts, and total protein (a marker of lung permeability) were assessed from bronchoalveolar lavage fluid (BALF). mRNA and protein levels of cellular mediators were determined from lung homogenates. We also utilized global mRNA expression analyses of lung tissue with Ingenuity Pathway Analyses (IPA) to identify patterns of gene expression through which IL-10 modifies O3-induced inflammation. Results: Mean numbers of BALF polymorphonuclear leukocytes (PMNs) were significantly greater in Il10-/- mice than in Il10+/+ mice after exposure to O3 at all time points tested. O3-enhanced nuclear NF-kB translocation was elevated in the lungs of Il10-/- compared to Il10+/+ mice. Gene expression analyses revealed several key IL-10 and O3-dependent mediators, including IL-6, MIP-2, IL-1 and CD86. Conclusions: Results indicated that IL-10 protects against O3-induced pulmonary neutrophilic inflammation and cell proliferation. Moreover, gene expression analyses identified three response pathways and several novel genetic targets (e.g. Ccr1, Socs3, Il33, Hat1, and Gale) through which IL10 may modulate the innate and adaptive immune response. These novel mechanisms of protection against the pathogenesis of O3-induced pulmonary inflammation may also provide potential therapeutic targets to protect susceptible individuals.
2011-10-19 | GSE25095 | GEO
Project description:We examined the role of miR-155 in differentiated Th17 cells during their induction of Experimental Autoimmune Encephalomyelitis (EAE). Using adoptive transfer experiments, we found that highly purified, MOG antigen specific Th17 cells lacking miR-155 are defective in their capacity to cause EAE. Gene expression profiling of purified miR-155-/- IL-17F+ Th17 cells identified a subset of effector genes that are dependent upon miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155-/- Th17 cells being hypo-responsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation, and finds that this occurs through a signaling network involving miR-155, Ets1 and the clinically relevant IL-23-IL-23R pathway. two biological replicates of miR-155-/- CD4+ IL-17F RFP+ T cells compared to two biological replicates of miR-155+/+CD4+IL-17F RFP+ T cells (as a control).
2013-05-01 | E-GEOD-45122 | biostudies-arrayexpress
Project description:We examined the role of miR-155 in differentiated Th17 cells during their induction of Experimental Autoimmune Encephalomyelitis (EAE). Using adoptive transfer experiments, we found that highly purified, MOG antigen specific Th17 cells lacking miR-155 are defective in their capacity to cause EAE. Gene expression profiling of purified miR-155-/- IL-17F+ Th17 cells identified a subset of effector genes that are dependent upon miR-155 for their proper expression through a mechanism involving repression of the transcription factor Ets1. Among the genes reduced in the absence of miR-155 was IL-23R, resulting in miR-155-/- Th17 cells being hypo-responsive to IL-23. Taken together, our study demonstrates a critical role for miR-155 in Th17 cells as they unleash autoimmune inflammation, and finds that this occurs through a signaling network involving miR-155, Ets1 and the clinically relevant IL-23-IL-23R pathway.
2013-05-01 | GSE45122 | GEO
Project description:Genome-wide analysis was performed on microRNA 155+/+ and -/- Th17 cells to determine the differentially expressed transcripts that are regulated by miR-155. We found that Jarid2 was differentially expressed in absence of miR-155 and highlight the mechanism for the silencing of IL-22 by Jarid2 and PRC2 in miR-155-/- Th17 cells.
2014-10-12 | GSE37228 | GEO
Project description:MicroRNA 155 (miR-155) has been shown to regulate the gene expression of important players of physiological and pathological processes, like hematopoietic lineage differentiation, immunity and inflammation, viral infections, cancer and cardiovascular diseases, among others. Degranulation is an event in which mast cells, upon activation of the FceRI, release their granule content rich in vasoactive amines, proteases and TNFa. Additionally activation of the receptor promotes de novo synthesis of cytokines, chemokines and growth factors. Analysis of bone marrow derived mast cells (BMMC) deficient in miR-155 showed a significant increase in FceRI mediated degranulation and in the release of cytokines like TNFa, IL-6 and IL-13. In addition miR 155-/- mice presented higher anaphylaxis reactions compared to WT mice. Gene expression analysis of BMMC was performed in order to identify intermediaries of FceRI mediated degranulation under the control of miR-155. The results indicate that miR-155 regulates negatively the expression of the regulatory subunits of the kinase PI3Kgamma, Pik3r5 (p101) and Pik3r6 (p84, p87PIKAP), involved in Ca+ influx and degranulation.
2014-03-20 | GSE56030 | GEO
Project description:MicroRNA 155 (miR-155) has been shown to regulate the gene expression of important players of physiological and pathological processes, like hematopoietic lineage differentiation, immunity and inflammation, viral infections, cancer and cardiovascular diseases, among others. Degranulation is an event in which mast cells, upon activation of the FceRI, release their granule content rich in vasoactive amines, proteases and TNFa. Additionally activation of the receptor promotes de novo synthesis of cytokines, chemokines and growth factors. Analysis of bone marrow derived mast cells (BMMC) deficient in miR-155 showed a significant increase in FceRI mediated degranulation and in the release of cytokines like TNFa, IL-6 and IL-13. In addition miR 155-/- mice presented higher anaphylaxis reactions compared to WT mice. Gene expression analysis of BMMC was performed in order to identify intermediaries of FceRI mediated degranulation under the control of miR-155. The results indicate that miR-155 regulates negatively the expression of the regulatory subunits of the kinase PI3Kgamma, Pik3r5 (p101) and Pik3r6 (p84, p87PIKAP), involved in Ca+ influx and degranulation. Total RNA from 3 independent cultures of WT and miR-155-/- BMMC treated with anti-DNP IgE and 20 ng/ml DNP-HSA for 1hr were used to performed gene expression analysis using the Affymetrix GenechipM-BM-. Mouse Gene 1.0 ST
2014-03-20 | E-GEOD-56030 | biostudies-arrayexpress