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Nan Shen - One of the best experts on this subject based on the ideXlab platform.
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333 in vivo therapeutic success of microrna 155 mir 155 antagomir in a mouse model of lupus alveolar haemorrhage
Lupus science & medicine, 2017Co-Authors: Shiyu Zhou, Nan ShenAbstract:Background and aims Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (MiR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. The purpose of this study was to examine the role of MiR-155 in the development of DAH in pristane-induced lupus using MiR-155-knockout (MiR-155-/-) mice and MiR-155 antagomir to silence MiR-155. Methods DAH was induced by an intraperitoneal injection of 0.5 mL of pristane. MiR-155 antagomir was intravenously administrated to silence MiR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analysed using Ingenuity Pathway Analysis. Real time q-PCR was used for single validation. Luciferase reporter assay and RNA-Ago2 immunoprecipitation were performed for target validation. Results MiR-155 expression was significantly increased in the development of DAH. Disease progression was reduced in MiR-155-/- mice and by in vivo silencing of MiR-155 using MiR-155 antagomir. MiR-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways, and reduced the expression of pro-inflammatory cytokines. Several negative regulators of nuclear factor (NF)-κB signalling were inhibited by pristane, and were re-activated in MiR-155-/- mice. In particular, the anti-inflammatory factor peroxisome proliferator-activated receptor-α was identified as a direct target of MiR-155. Conclusions MiR-155 promotes pristane-induced lung inflammation. MiR-155 contributes to ectopic activation of NF-κB signalling pathways by targeting multiple negative regulators. MiR-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
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in vivo silencing of microrna 155 mir 155 ameliorated pulmonary hemorrhage induced by pristane ba12p 100 ba12p 100
Journal of Immunology, 2014Co-Authors: Xinfang Huang, Shiyu Zhou, Nan Shen, John B Harley, Dong LiangAbstract:Background: MiR-155 is a typical pleiotropic miRNA that participates in various aspects of immunity. In this study, we systemically examined the role of MiR-155 in the development of pulmonary hemorrhage (PH) in Pristane-induced lupus. Methods: Mice received a single i.p injection of 0.5 ml Pristane. 2 weeks later, lung tissues were collected for pathologic assessment. Total lung RNAs were assayed by qPCR or subjected to gene profiling. Gene profiling data was analyzed by IPA software. Serum cytokines were messured by Bio-plex Assays. Results: We showed that MiR-155 was elevated in lung tissues after Pristane treatment. MiR-155 KO mice appeared to develop attenuated PH, with reduced levels of pro-inflammatory cytokines (TNF-a, IL-6). By integrating the gene expression profiling data from MiR-155 KO mice with microRNA target predication, our data suggest that PPARα, an anti-inflammatory transcription factor, is a novel functional target of MiR-155. Furthermore, we showed that in vivo silencing of MiR-155 by MiR-155 antagomir significantly ameliorated PH induced by Pristane. Consistently, the pro-inflammatory cytokines (TNF-a, IL-6) were reduced upon MiR-155 silencing. Conclusion: Overall, our study shows that knockdown of MiR-155 by MiR-155 antagomir inhibits Pristane induced PH through reducing the production of pro-inflammatory cytokines. This finding suggests a promising therapeutic potential of MiR-155 antagonist in the treatment of acute lung inflammation in lupus.
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mir 155 and its star form partner mir 155 cooperatively regulate type i interferon production by human plasmacytoid dendritic cells
Blood, 2010Co-Authors: Haibo Zhou, Yuanjia Tang, Xinfang Huang, Huijuan Cui, Xiaobing Luo, Shunle Chen, Nan ShenAbstract:The recent discovery of microRNAs (miRNAs) has revealed a new layer of gene expression regulation, affecting the immune system. Here, we identify their roles in regulating human plasmacytoid dendritic cell (PDC) activation. miRNA profiling showed the significantly differential expression of 19 miRNAs in PDCs after Toll-like receptor 7 (TLR7) stimulation, among which MiR-155* and MiR-155 were the most highly induced. Although they were processed from a single precursor and were both induced by TLR7 through the c-Jun N-terminal kinase pathway, MiR-155* and MiR-155 had opposite effects on the regulation of type I interferon production by PDC. Further study indicated that MiR-155* augmented interferon-α/β expression by suppressing IRAKM, whereas MiR-155 inhibited their expression by targeting TAB2. Kinetic analysis of MiR-155* and MiR-155 induction revealed that MiR-155* was mainly induced in the early stage of stimulation, and that MiR-155 was mainly induced in the later stage, suggesting their cooperative involvement in PDC activation. Finally, we demonstrated that MiR-155* and MiR-155 were inversely regulated by autocrine/paracrine type I interferon and TLR7-activated KHSRP at the posttranscriptional level, which led to their different dynamic induction by TLR7. Thus, our study identified and validated novel miRNA-protein networks involved in regulating PDC activation.
Shiyu Zhou - One of the best experts on this subject based on the ideXlab platform.
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333 in vivo therapeutic success of microrna 155 mir 155 antagomir in a mouse model of lupus alveolar haemorrhage
Lupus science & medicine, 2017Co-Authors: Shiyu Zhou, Nan ShenAbstract:Background and aims Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (MiR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. The purpose of this study was to examine the role of MiR-155 in the development of DAH in pristane-induced lupus using MiR-155-knockout (MiR-155-/-) mice and MiR-155 antagomir to silence MiR-155. Methods DAH was induced by an intraperitoneal injection of 0.5 mL of pristane. MiR-155 antagomir was intravenously administrated to silence MiR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analysed using Ingenuity Pathway Analysis. Real time q-PCR was used for single validation. Luciferase reporter assay and RNA-Ago2 immunoprecipitation were performed for target validation. Results MiR-155 expression was significantly increased in the development of DAH. Disease progression was reduced in MiR-155-/- mice and by in vivo silencing of MiR-155 using MiR-155 antagomir. MiR-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways, and reduced the expression of pro-inflammatory cytokines. Several negative regulators of nuclear factor (NF)-κB signalling were inhibited by pristane, and were re-activated in MiR-155-/- mice. In particular, the anti-inflammatory factor peroxisome proliferator-activated receptor-α was identified as a direct target of MiR-155. Conclusions MiR-155 promotes pristane-induced lung inflammation. MiR-155 contributes to ectopic activation of NF-κB signalling pathways by targeting multiple negative regulators. MiR-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
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in vivo therapeutic success of microrna 155 antagomir in a mouse model of lupus alveolar hemorrhage
Arthritis & Rheumatism, 2016Co-Authors: Shiyu Zhou, Chunyuan Xiao, Xinfang Huang, Brandon W Higgs, Bahija Jallal, Philip Brohawn, Bo Qu, Yao Meng, Yuanjia TangAbstract:Objective Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Pristane-treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA-155 (MiR-155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of MiR-155 in various autoimmune disorders. The purpose of this study was to examine the role of MiR-155 in the development of DAH in pristane-induced lupus using MiR-155–knockout (MiR-155−/−) mice and MiR-155 antagomir to silence MiR-155. Methods DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA-155 antagomir was administered intravenously to silence MiR-155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real-time quantitative polymerase chain reaction analysis was used for single-gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. Results MicroRNA-155 expression was significantly increased during the development of DAH. Disease progression was reduced in MiR-155−/− mice as well as by in vivo silencing of MiR-155 using a MiR-155 antagomir. MicroRNA-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF-κB signaling were inhibited by pristane and were reactivated in MiR-155−/− mice. In particular, the antiinflammatory factor peroxisome proliferator–activated receptor α was identified as a direct target of MiR-155. Conclusion MicroRNA-155 promotes pristane-induced lung inflammation. It contributes to ectopic activation of NF-κB signaling pathways by targeting multiple negative regulators. MicroRNA-155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
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in vivo silencing of microrna 155 mir 155 ameliorated pulmonary hemorrhage induced by pristane ba12p 100 ba12p 100
Journal of Immunology, 2014Co-Authors: Xinfang Huang, Shiyu Zhou, Nan Shen, John B Harley, Dong LiangAbstract:Background: MiR-155 is a typical pleiotropic miRNA that participates in various aspects of immunity. In this study, we systemically examined the role of MiR-155 in the development of pulmonary hemorrhage (PH) in Pristane-induced lupus. Methods: Mice received a single i.p injection of 0.5 ml Pristane. 2 weeks later, lung tissues were collected for pathologic assessment. Total lung RNAs were assayed by qPCR or subjected to gene profiling. Gene profiling data was analyzed by IPA software. Serum cytokines were messured by Bio-plex Assays. Results: We showed that MiR-155 was elevated in lung tissues after Pristane treatment. MiR-155 KO mice appeared to develop attenuated PH, with reduced levels of pro-inflammatory cytokines (TNF-a, IL-6). By integrating the gene expression profiling data from MiR-155 KO mice with microRNA target predication, our data suggest that PPARα, an anti-inflammatory transcription factor, is a novel functional target of MiR-155. Furthermore, we showed that in vivo silencing of MiR-155 by MiR-155 antagomir significantly ameliorated PH induced by Pristane. Consistently, the pro-inflammatory cytokines (TNF-a, IL-6) were reduced upon MiR-155 silencing. Conclusion: Overall, our study shows that knockdown of MiR-155 by MiR-155 antagomir inhibits Pristane induced PH through reducing the production of pro-inflammatory cytokines. This finding suggests a promising therapeutic potential of MiR-155 antagonist in the treatment of acute lung inflammation in lupus.
Jason Ioannidis - One of the best experts on this subject based on the ideXlab platform.
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a mirna target network putatively involved in follicular atresia
Domestic Animal Endocrinology, 2017Co-Authors: F X Donadeu, Bushra T Mohammed, Jason IoannidisAbstract:Abstract In a previous microarray study, we identified a subset of micro RNAS (miRNAs), which expression was distinctly higher in atretic than healthy follicles of cattle. In the present study, we investigated the involvement of those miRNAs in granulosa and theca cells during atresia. Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) confirmed that miR-21-5p/-3p, miR-150, miR-409a, miR-142-5p, miR-378, miR-222, MiR-155, and miR-199a-5p were expressed at higher levels in atretic than healthy follicles (9–17 mm, classified based on steroidogenic capacity). All miRNAs except miR-21-3p and miR-378 were expressed at higher levels in theca than granulosa cells. The expression of 13 predicted miRNA targets was determined in follicular cells by RT-qPCR, revealing downregulation of HIF1A , ETS1 , JAG1 , VEGFA , and MSH2 in either or both cell types during atresia. Based on increases in miRNA levels simultaneous with decreases in target levels in follicular cells, several predicted miRNA target interactions were confirmed that are putatively involved in follicular atresia, namely miR-199a-5p/MiR-155- HIF1A in granulosa cells, MiR-155/miR-222- ETS1 in theca cells, miR-199a-5p- JAG1 in theca cells, miR-199a-5p/miR-150/miR-378- VEGFA in granulosa and theca cells, and MiR-155- MSH2 in theca cells. These results offer novel insight on the involvement of miRNAs in follicle development by identifying a miRNA target network that is putatively involved in follicle atresia.
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a mirna target network putatively involved in follicular atresia
Domestic Animal Endocrinology, 2017Co-Authors: F X Donadeu, Bushra T Mohammed, Jason IoannidisAbstract:Abstract In a previous microarray study, we identified a subset of micro RNAS (miRNAs), which expression was distinctly higher in atretic than healthy follicles of cattle. In the present study, we investigated the involvement of those miRNAs in granulosa and theca cells during atresia. Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) confirmed that miR-21-5p/-3p, miR-150, miR-409a, miR-142-5p, miR-378, miR-222, MiR-155, and miR-199a-5p were expressed at higher levels in atretic than healthy follicles (9–17 mm, classified based on steroidogenic capacity). All miRNAs except miR-21-3p and miR-378 were expressed at higher levels in theca than granulosa cells. The expression of 13 predicted miRNA targets was determined in follicular cells by RT-qPCR, revealing downregulation of HIF1A , ETS1 , JAG1 , VEGFA , and MSH2 in either or both cell types during atresia. Based on increases in miRNA levels simultaneous with decreases in target levels in follicular cells, several predicted miRNA target interactions were confirmed that are putatively involved in follicular atresia, namely miR-199a-5p/MiR-155- HIF1A in granulosa cells, MiR-155/miR-222- ETS1 in theca cells, miR-199a-5p- JAG1 in theca cells, miR-199a-5p/miR-150/miR-378- VEGFA in granulosa and theca cells, and MiR-155- MSH2 in theca cells. These results offer novel insight on the involvement of miRNAs in follicle development by identifying a miRNA target network that is putatively involved in follicle atresia.
Dinesh S Rao - One of the best experts on this subject based on the ideXlab platform.
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microrna 155 promotes autoimmune inflammation by enhancing inflammatory t cell development
Immunity, 2010Co-Authors: Ryan M Oconnell, Aadel A Chaudhuri, Dinesh S Rao, Daniel Kahn, William S Gibson, June L Round, Rebecca L Scholz, Melissa KahnAbstract:Mammalian noncoding microRNAs (miRNAs) are a class of gene regulators that have been linked to immune system function. Here, we have investigated the role of MiR-155 during an autoimmune inflammatory disease. Consistent with a positive role for MiR-155 in mediating inflammatory responses, Mir155^(−/−) mice were highly resistant to experimental autoimmune encephalomyelitis (EAE). MiR-155 functions in the hematopoietic compartment to promote the development of inflammatory T cells including the T helper 17 (Th17) cell and Th1 cell subsets. Furthermore, the major contribution of MiR-155 to EAE was CD4^+ T cell intrinsic, whereas MiR-155 was also required for optimum dendritic cell production of cytokines that promoted Th17 cell formation. Our study shows that one aspect of MiR-155 function is the promotion of T cell-dependent tissue inflammation, suggesting that MiR-155 might be a promising therapeutic target for the treatment of autoimmune disorders.
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inositol phosphatase ship1 is a primary target of mir 155
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Rya M Oconnell, Aadel A Chaudhuri, Dinesh S Rao, David AltimoreAbstract:MicroRNA-155 (MiR-155) has emerged as a critical regulator of immune cell development, function, and disease. However, the mechanistic basis for its impact on the hematopoietic system remains largely unresolved. Because miRNAs function by repressing specific mRNAs through direct 3′UTR interactions, we have searched for targets of MiR-155 implicated in the regulation of hematopoiesis. In the present study, we identify Src homology-2 domain-containing inositol 5-phosphatase 1 (SHIP1) as a direct target of MiR-155, and, using gain and loss of function approaches, show that MiR-155 represses SHIP1 through direct 3′UTR interactions that have been highly conserved throughout evolution. Repression of endogenous SHIP1 by MiR-155 occurred following sustained over-expression of MiR-155 in hematopoietic cells both in vitro and in vivo, and resulted in increased activation of the kinase Akt during the cellular response to LPS. Furthermore, SHIP1 was also repressed by physiologically regulated MiR-155, which was observed in LPS-treated WT versus MiR-155−/− primary macrophages. In mice, specific knockdown of SHIP1 in the hematopoietic system following retroviral delivery of a MiR-155-formatted siRNA against SHIP1 resulted in a myeloproliferative disorder, with striking similarities to that observed in MiR-155-expressing mice. Our study unveils a molecular link between MiR-155 and SHIP1 and provides evidence that repression of SHIP1 is an important component of MiR-155 biology.
Parvathi Ranganathan - One of the best experts on this subject based on the ideXlab platform.
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microrna 155 modulates acute graft versus host disease by impacting t cell expansion migration and effector function
Journal of Immunology, 2018Co-Authors: Nina C Zitzer, Patricia A Taylor, Katiri Snyder, Xiamoei Meng, Yvonne A Efebera, Steven M Devine, Bruce R Blazar, Ramiro Garzon, Parvathi RanganathanAbstract:MicroRNA-155 (MiR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that MiR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving MiR-155-deficient (miR155-/-) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which MiR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that MiR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that MiR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8+ donor T cells and promoting exhaustion in donor CD4+ T cells in both the spleen and colon. Additionally, MiR-155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and MiR-155-/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that MiR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that MiR-155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of MiR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration.
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regulation of acute graft versus host disease by microrna 155
Blood, 2010Co-Authors: Parvathi Ranganathan, Catherine E A Heaphy, Stefan Costinean, Nicole Stauffer, Caroline Na, Mehdi Hamadani, Ramasamy Santhanam, Patricia A Taylor, Sukhinder K Sandhu, Gang HeAbstract:Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic stem cell transplant (alloHSCT), underscoring the need to further elucidate its mechanisms and develop novel treatments. Based on recent observations that microRNA-155 (MiR-155) is up-regulated during T-cell activation, we hypothesized that MiR-155 is involved in the modulation of aGVHD. Here we show that MiR-155 expression was up-regulated in T cells from mice developing aGVHD after alloHSCT. Mice receiving MiR-155–deficient donor lymphocytes had markedly reduced lethal aGVHD, whereas lethal aGVHD developed rapidly in mice recipients of MiR-155 overexpressing T cells. Blocking MiR-155 expression using a synthetic anti–MiR-155 after alloHSCT decreased aGVHD severity and prolonged survival in mice. Finally, MiR-155 up-regulation was shown in specimens from patients with pathologic evidence of intestinal aGVHD. Altogether, our data indicate a role for MiR-155 in the regulation of GVHD and point to MiR-155 as a novel target for therapeutic intervention in this disease.