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Westley H Reeves - One of the best experts on this subject based on the ideXlab platform.

  • toll like receptor 7 stimulated tumor necrosis factor α causes bone marrow damage in systemic lupus erythematosus
    Arthritis & Rheumatism, 2014
    Co-Authors: Haoyang Zhuang, Yuan Xu, Yi Li, Hai Wang, Lijun Yang, Westley H Reeves
    Abstract:

    Objective To define the pathogenesis of bone marrow (BM) involvement in systemic lupus erythematosus (SLE). Methods Tumor necrosis factor α (TNFα) levels, cell death, and cellular damage in BM from SLE patients, controls, and mice with Pristane-induced lupus were analyzed using a morphometric technique and immunohistochemistry. The pathogenesis of BM abnormalities was studied in wild-type (WT), TNFα−/−, Toll-like receptor–deficient (TLR-7−/−), interferon (IFN)–α/β/ω receptor–knockout (IFNAR−/−), and B cell–deficient (μmt) mice treated with Pristane. Flow cytometry was used to examine TNFα production (by intracellular staining) and plasma cell/plasmablast development. CXCL12 expression was determined by quantitative polymerase chain reaction. Results BM from SLE patients exhibited striking death of niche and hematopoietic cells associated with TNFα overproduction. BM from mice with a type I IFN–mediated lupus syndrome induced by Pristane showed similar abnormalities. TNFα was produced mainly by BM neutrophils, many with phagocytosed nuclear material (lupus erythematosus cells). TNFα production was abolished in Pristane-treated TLR-7−/− and μmt mice but was restored in μmt mice by infusing normal plasma. Pristane-treated WT and IFNAR−/− mice developed anemia, BM hypocellularity, and extramedullary hematopoiesis, which were absent in TLR-7−/− and TNFα−/− mice. Additionally, the expression of CXCL12, which is produced by stromal cells and mediates homing of hematopoietic cells and plasmablasts, was decreased in BM from Pristane-treated WT mice but was normal in BM from Pristane-treated TNFα−/− mice. Conclusion Although autoantibodies and glomerulonephritis are type I IFN dependent, lupus-associated BM abnormalities were TLR-7 and TNFα driven but type I IFN independent, suggesting that lupus is a disorder of innate immunity in which TLR-7 activation by phagocytosed nuclei causes relentless type I IFN and TNFα production mediating glomerulonephritis and hematologic involvement, respectively.

  • The role of B-cell subsets in Pristane-induced lupus (130.14)
    Journal of Immunology, 2007
    Co-Authors: Tolga Barker, Dina C Nacionales, Westley H Reeves, Jason S. Weinstein, Kindra M. Kelly-scumpia, Eric S. Sobel, Minoru Satoh
    Abstract:

    An intraperitoneal (ip) injection of Pristane in mice induces a biphasic immune response characterized by an early T-independent phase (increased total IgM, IgM anti-ssDNA peaking at 2 wks) and a later T-dependent phase (increased total IgG, IgG anti-snRNPs, Su, chromatin after 4–6 wks). Although peritoneal B-1 cells are thought to be responsible for the early phase, they disappear after ip Pristane. IgG autoantibodies can be produced in SCID mice by transferring peritoneal, spleen, or lymph node cells from Pristane-treated mice. To evaluate further the role of B-cell subsets in the two phases of Pristane-induced autoimmunity, GFP+ naive peritoneal, spleen, or bone marrow (bm) cells were transferred ip to T- and B-cell deficient RAG1−/− mice, followed by an ip Pristane 3 days later. Autoantibodies and total Ig (ELISA), and the phenotypes of GFP+ cells in the recipients (flow cytometry) were analyzed. At 3 days prior to Pristane ip, GFP+ peritoneal B-1 cells (CD19+CD11b+ CD5+ IgM+) were detected in recipients of bm, peritoneal, or spleen cells. Following Pristane ip, peritoneal B-1 cells disappeared, as seen in immunocompetent mice. Analysis of GFP+ cells in peritoneal cavity at day 10 revealed the predominance of CD11b+ macrophages in the peritoneal cell recipients whereas T and B cells were predominant in bm or spleen cell recipients. In mice that received GFP+ spleen cells, IgM anti-ss- and -dsDNA dramatically increased at 2–4 weeks after Pristane, while the total IgM levels increased in all groups at later time points. We conclude that splenic B cells may be responsible for the early IgM response in Pristane model. Supported by NIH

  • Pristane induced autoimmunity in germ free mice
    Clinical Immunology, 2005
    Co-Authors: Akiei Mizutani, Victoria M Shaheen, Hideo Yoshida, Jun Akaogi, Yoshiki Kuroda, Dina C Nacionales, Yoshioki Yamasaki, Michito Hirakata, Westley H Reeves, Minoru Satoh
    Abstract:

    Hypergammaglobulinemia and autoantibodies are reduced in Pristane-treated specific pathogen-free mice vs. conventionally housed controls, consistent with the role of microbial stimulation in this model. To determine whether microbial stimulation is required, BALB/c mice housed under germ-free conditions were treated i.p. with sterile PBS or Pristane and examined 6 months later. As in conventional mice, Pristane-treated germ-free mice developed peritoneal granulomas and hypergammaglobulinemia with increased IgG2a/IgG1 ratios. LPS stimulation induced more IL-6, IL-12, and TNF-α, and anti-CD3 induced more IFN-γ and IL-4 by peritoneal cells from Pristane-treated mice vs. control. Anti-nRNP/Sm and -Su autoantibodies were found in 40% and 43%, respectively, of Pristane-treated germ-free mice by immunoprecipitation. Thus, bacterial stimulation was not required for lupus autoantibodies, peritoneal granuloma formation, hypergammaglobulinemia, or cytokine overproduction. Although microbial stimulation acts synergistically with Pristane, these results clearly indicate that Pristane does not act merely by increasing exposure to microbial products such as LPS.

  • x linked immunodeficient mice spontaneously produce lupus related anti rna helicase a autoantibodies but are resistant to Pristane induced lupus
    International Immunology, 2003
    Co-Authors: Minoru Satoh, Akiei Mizutani, Hideo Yoshida, Jun Akaogi, Yoshiki Kuroda, Dina C Nacionales, Michito Hirakata, Krista M Behney, Westley H Reeves
    Abstract:

    Murine lupus can occur spontaneously or be induced by hydrocarbons, such as Pristane. Spontaneous disease in MRL and NZB/W F1 mice is suppressed by the xid (X-linked immunodeficiency) mutation, which greatly diminishes T cell-independent type 2 responses as well as the number of peritoneal B1 cells. The present study asked whether lupus induced by i.p. injection of Pristane likewise is inhibited by the xid defect. Male CBA/N (xid) mice were refractory to the induction of autoantibodies by Pristane, whereas 23% of Pristane-treated male CBA/CaJ controls produced anti-nRNP/Sm, -Su and/or -OJ (isoleucyl tRNA synthetase) antibodies. Unexpectedly, 43% (12 of 28) of the xid mice spontaneously produced anti-nuclear antibodies that proved highly specific for the lupus antigen RNA helicase A (RHA). Strikingly, this specificity was absent in CBA/CaJ mice (none of 51). Moreover, Pristane treatment suppressed the production of anti-RHA antibodies when administered prior to the onset of autoantibody production, but enhanced anti-RHA levels when given after the onset of autoantibody production, suggesting that Pristane interferes with anti-RHA production at an early stage. Large amounts of IgG1 anti-RHA autoantibodies were detected in the sera of xid mice, whereas Pristane-induced anti-nRNP/Sm and -Su autoantibodies were almost exclusively IgG2a. Cytokine production within the peritoneal cavity reflected the predominant isotypes: IL-12 and IFN-g predominated in Pristane-treated mice, whereas IL-4 and IL-6 were more predominant in untreated xid mice. The spontaneous production of antiRHA by xid mice and its suppression by Pristane treatment at the level of autoantibody induction supports the idea that lupus autoantibodies may be generated through a variety of mechanisms.

  • nephritogenic autoantibodies but absence of nephritis in il 12p35 deficient mice with Pristane induced lupus
    Kidney International, 2003
    Co-Authors: Nicola Calvani, Westley H Reeves, Minoru Satoh, Byron P Croker, Hanno B Richards
    Abstract:

    Nephritogenic autoantibodies but absence of nephritis in Il-12p35–deficient mice with Pristane-induced lupus. Background There is strong evidence that Th1 cytokines are essential for disease in murine models of lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-γ (IFN-γ) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of lupus, although its precise role remains unclear. We investigated the role of IL-12 for lupus-like disease induced by Pristane. IL-12p35–deficient (-/-) and control (+/+) BALB/c mice were treated with Pristane or phosphate-buffered saline (PBS). Methods Proteinuria was measured and renal pathology evaluated 10 months after treatment. Sera were analyzed for autoantibodies and total immunoglobulin levels. Cytokine expression and production was analyzed. Results Pristane induced nephritogenic autoantibodies and renal immunoglobulin and complement deposition in both IL-12 -/- and +/+ mice. However, proliferative pathology and proteinuria were absent in IL-12-/- mice, whereas Pristane induced severe nephritis in one third of the +/+ mice. As expected, cytokine balance was skewed toward a Th2 response in Pristane-treated IL-12 -/- mice. Conclusion These data indicate that renal immune complex deposition can occur in the absence of IL-12p35, but that structural renal damage requires the presence of IL-12p35 or mediators induced by this molecule, such as IFN-γ. In contrast to the abrogation of nephritogenic autoantibodies by the lack of IFN-γ, such antibodies are induced by Pristane in IL-12p35–deficient mice. Absence of structural renal disease, despite the presence of nephritogenic autoantibodies in Pristane-treated IL-12-/- mice, indicates that antibody deposition alone is not sufficient for the development of lupus nephritis in this model.

Minoru Satoh - One of the best experts on this subject based on the ideXlab platform.

  • The role of B-cell subsets in Pristane-induced lupus (130.14)
    Journal of Immunology, 2007
    Co-Authors: Tolga Barker, Dina C Nacionales, Westley H Reeves, Jason S. Weinstein, Kindra M. Kelly-scumpia, Eric S. Sobel, Minoru Satoh
    Abstract:

    An intraperitoneal (ip) injection of Pristane in mice induces a biphasic immune response characterized by an early T-independent phase (increased total IgM, IgM anti-ssDNA peaking at 2 wks) and a later T-dependent phase (increased total IgG, IgG anti-snRNPs, Su, chromatin after 4–6 wks). Although peritoneal B-1 cells are thought to be responsible for the early phase, they disappear after ip Pristane. IgG autoantibodies can be produced in SCID mice by transferring peritoneal, spleen, or lymph node cells from Pristane-treated mice. To evaluate further the role of B-cell subsets in the two phases of Pristane-induced autoimmunity, GFP+ naive peritoneal, spleen, or bone marrow (bm) cells were transferred ip to T- and B-cell deficient RAG1−/− mice, followed by an ip Pristane 3 days later. Autoantibodies and total Ig (ELISA), and the phenotypes of GFP+ cells in the recipients (flow cytometry) were analyzed. At 3 days prior to Pristane ip, GFP+ peritoneal B-1 cells (CD19+CD11b+ CD5+ IgM+) were detected in recipients of bm, peritoneal, or spleen cells. Following Pristane ip, peritoneal B-1 cells disappeared, as seen in immunocompetent mice. Analysis of GFP+ cells in peritoneal cavity at day 10 revealed the predominance of CD11b+ macrophages in the peritoneal cell recipients whereas T and B cells were predominant in bm or spleen cell recipients. In mice that received GFP+ spleen cells, IgM anti-ss- and -dsDNA dramatically increased at 2–4 weeks after Pristane, while the total IgM levels increased in all groups at later time points. We conclude that splenic B cells may be responsible for the early IgM response in Pristane model. Supported by NIH

  • Pristane induced autoimmunity in germ free mice
    Clinical Immunology, 2005
    Co-Authors: Akiei Mizutani, Victoria M Shaheen, Hideo Yoshida, Jun Akaogi, Yoshiki Kuroda, Dina C Nacionales, Yoshioki Yamasaki, Michito Hirakata, Westley H Reeves, Minoru Satoh
    Abstract:

    Hypergammaglobulinemia and autoantibodies are reduced in Pristane-treated specific pathogen-free mice vs. conventionally housed controls, consistent with the role of microbial stimulation in this model. To determine whether microbial stimulation is required, BALB/c mice housed under germ-free conditions were treated i.p. with sterile PBS or Pristane and examined 6 months later. As in conventional mice, Pristane-treated germ-free mice developed peritoneal granulomas and hypergammaglobulinemia with increased IgG2a/IgG1 ratios. LPS stimulation induced more IL-6, IL-12, and TNF-α, and anti-CD3 induced more IFN-γ and IL-4 by peritoneal cells from Pristane-treated mice vs. control. Anti-nRNP/Sm and -Su autoantibodies were found in 40% and 43%, respectively, of Pristane-treated germ-free mice by immunoprecipitation. Thus, bacterial stimulation was not required for lupus autoantibodies, peritoneal granuloma formation, hypergammaglobulinemia, or cytokine overproduction. Although microbial stimulation acts synergistically with Pristane, these results clearly indicate that Pristane does not act merely by increasing exposure to microbial products such as LPS.

  • x linked immunodeficient mice spontaneously produce lupus related anti rna helicase a autoantibodies but are resistant to Pristane induced lupus
    International Immunology, 2003
    Co-Authors: Minoru Satoh, Akiei Mizutani, Hideo Yoshida, Jun Akaogi, Yoshiki Kuroda, Dina C Nacionales, Michito Hirakata, Krista M Behney, Westley H Reeves
    Abstract:

    Murine lupus can occur spontaneously or be induced by hydrocarbons, such as Pristane. Spontaneous disease in MRL and NZB/W F1 mice is suppressed by the xid (X-linked immunodeficiency) mutation, which greatly diminishes T cell-independent type 2 responses as well as the number of peritoneal B1 cells. The present study asked whether lupus induced by i.p. injection of Pristane likewise is inhibited by the xid defect. Male CBA/N (xid) mice were refractory to the induction of autoantibodies by Pristane, whereas 23% of Pristane-treated male CBA/CaJ controls produced anti-nRNP/Sm, -Su and/or -OJ (isoleucyl tRNA synthetase) antibodies. Unexpectedly, 43% (12 of 28) of the xid mice spontaneously produced anti-nuclear antibodies that proved highly specific for the lupus antigen RNA helicase A (RHA). Strikingly, this specificity was absent in CBA/CaJ mice (none of 51). Moreover, Pristane treatment suppressed the production of anti-RHA antibodies when administered prior to the onset of autoantibody production, but enhanced anti-RHA levels when given after the onset of autoantibody production, suggesting that Pristane interferes with anti-RHA production at an early stage. Large amounts of IgG1 anti-RHA autoantibodies were detected in the sera of xid mice, whereas Pristane-induced anti-nRNP/Sm and -Su autoantibodies were almost exclusively IgG2a. Cytokine production within the peritoneal cavity reflected the predominant isotypes: IL-12 and IFN-g predominated in Pristane-treated mice, whereas IL-4 and IL-6 were more predominant in untreated xid mice. The spontaneous production of antiRHA by xid mice and its suppression by Pristane treatment at the level of autoantibody induction supports the idea that lupus autoantibodies may be generated through a variety of mechanisms.

  • nephritogenic autoantibodies but absence of nephritis in il 12p35 deficient mice with Pristane induced lupus
    Kidney International, 2003
    Co-Authors: Nicola Calvani, Westley H Reeves, Minoru Satoh, Byron P Croker, Hanno B Richards
    Abstract:

    Nephritogenic autoantibodies but absence of nephritis in Il-12p35–deficient mice with Pristane-induced lupus. Background There is strong evidence that Th1 cytokines are essential for disease in murine models of lupus. Interleukin-12 (IL-12) is essential for Th1 cell differentiation and induces interferon-γ (IFN-γ) production. Paradoxically, it has been suggested that an IL-12 defect drives the pathogenesis of lupus, although its precise role remains unclear. We investigated the role of IL-12 for lupus-like disease induced by Pristane. IL-12p35–deficient (-/-) and control (+/+) BALB/c mice were treated with Pristane or phosphate-buffered saline (PBS). Methods Proteinuria was measured and renal pathology evaluated 10 months after treatment. Sera were analyzed for autoantibodies and total immunoglobulin levels. Cytokine expression and production was analyzed. Results Pristane induced nephritogenic autoantibodies and renal immunoglobulin and complement deposition in both IL-12 -/- and +/+ mice. However, proliferative pathology and proteinuria were absent in IL-12-/- mice, whereas Pristane induced severe nephritis in one third of the +/+ mice. As expected, cytokine balance was skewed toward a Th2 response in Pristane-treated IL-12 -/- mice. Conclusion These data indicate that renal immune complex deposition can occur in the absence of IL-12p35, but that structural renal damage requires the presence of IL-12p35 or mediators induced by this molecule, such as IFN-γ. In contrast to the abrogation of nephritogenic autoantibodies by the lack of IFN-γ, such antibodies are induced by Pristane in IL-12p35–deficient mice. Absence of structural renal disease, despite the presence of nephritogenic autoantibodies in Pristane-treated IL-12-/- mice, indicates that antibody deposition alone is not sufficient for the development of lupus nephritis in this model.

  • widespread susceptibility among inbred mouse strains to the induction of lupus autoantibodies by Pristane
    Clinical and Experimental Immunology, 2000
    Co-Authors: Minoru Satoh, Victoria M Shaheen, Hideo Yoshida, Hanno B Richards, M Shaw, J O Naim, P H Wooley, Westley H Reeves
    Abstract:

    Unlike other agents associated with drug-induced lupus, the isoprenoid alkane Pristane induces autoantibodies pathognomonic of lupus, including anti-Sm, anti-dsDNA, and anti-ribosomal P in BALB/c and SJL/J mice. The susceptibility of other strains of mice to Pristane-induced lupus is unknown and is the focus of the present study. Anti-nRNP/Sm, anti-Su, and anti-ribosomal P autoantibodies were produced by most strains of mice surveyed within several months of Pristane treatment, although there was marked interstrain variability in their frequencies, levels, and times of onset. In sharp contrast, the production of autoantibodies against the double-stranded RNA binding proteins NF45/NF90/p110 was restricted to B6 and B10.S mice. We conclude that Pristane selectively induces lupus-specific autoantibodies in virtually any strain of mouse regardless of its genetic background. However, H-2-linked as well as non-H2 genes influenced the expression of individual autoantibody markers. The widespread susceptibility of Pristane-treated mice to lupus autoantibody production and the relatively small effect of MHC are unique features of this chemically induced lupus syndrome, with potential implications for understanding the pathogenesis of autoantibodies in idiopathic human systemic lupus erythematosus.

Frieder Schauer - One of the best experts on this subject based on the ideXlab platform.

  • degradation of the multiple branched alkane 2 6 10 14 tetramethyl pentadecane Pristane in rhodococcus ruber and mycobacterium neoaurum
    International Biodeterioration & Biodegradation, 2009
    Co-Authors: Le Thi Nhicong, Annett Mikolasch, Hans-peter Klenk, Frieder Schauer
    Abstract:

    Abstract Pristane, a highly branched hydrocarbon that also contains iso -branched termini, was used as a substrate for several alkane-metabolizing bacteria. Rhodococcus ruber and Mycobacterium neoaurum were able to utilize Pristane for growth effectively. The intermediates produced by these bacteria during incubation with Pristane were analyzed by gas chromatography (GC) and gas chromatography/mass spectra (GC/MS). The products revealed as products of 4-methyl pentanoic acid; methyl butanedioic acid; 2-methyl pentadioic acid; methyl propanedioic acid; 4-methyl heptanedioic acid; and 2,6,10,14-tetramethyl-pentadecan-3-one were detected in M. neoaurum cultures. In R. ruber , methyl butanedioic acid; 2-methyl pentadioic acid; 4,8-dimethylnonanoic acid, 4-methyl heptanedioic acid; 2,6,10-trimethylundecanoic acid; 3,7-dimethyl decanedioic acid; and 2,6,10,14-tetramethyl-pentadecan-3-one were detected. The occurrence of these intermediates showed that Pristane could be catabolized not only via mono- but also by a di-terminal oxidation pathway. Furthermore, the presence of 2,6,10,14-tetramethyl-pentadecan-3-one; 3,7-dimethyldecandioate; and 2-methylbutandioate established a third pathway initiated by sub-terminal oxidation at the third carbon atom of Pristane. Novel intermediates detected suggest simultaneous sub-terminal and di-terminal oxidation pathways.

  • Degradation of the multiple branched alkane 2,6,10,14-tetramethyl-pentadecane (Pristane) in Rhodococcus ruber and Mycobacterium neoaurum
    International Biodeterioration and Biodegradation, 2009
    Co-Authors: Le Thi Nhi-cong, Annett Mikolasch, Hans-peter Klenk, Frieder Schauer
    Abstract:

    Pristane, a highly branched hydrocarbon that also contains iso-branched termini, was used as a substrate for several alkane-metabolizing bacteria. Rhodococcus ruber and Mycobacterium neoaurum were able to utilize Pristane for growth effectively. The intermediates produced by these bacteria during incubation with Pristane were analyzed by gas chromatography (GC) and gas chromatography/mass spectra (GC/MS). The products revealed as products of 4-methyl pentanoic acid; methyl butanedioic acid; 2-methyl pentadioic acid; methyl propanedioic acid; 4-methyl heptanedioic acid; and 2,6,10,14-tetramethyl-pentadecan-3-one were detected in M. neoaurum cultures. In R. ruber, methyl butanedioic acid; 2-methyl pentadioic acid; 4,8-dimethylnonanoic acid, 4-methyl heptanedioic acid; 2,6,10-trimethylundecanoic acid; 3,7-dimethyl decanedioic acid; and 2,6,10,14-tetramethyl-pentadecan-3-one were detected. The occurrence of these intermediates showed that Pristane could be catabolized not only via mono- but also by a di-terminal oxidation pathway. Furthermore, the presence of 2,6,10,14-tetramethyl-pentadecan-3-one; 3,7-dimethyldecandioate; and 2-methylbutandioate established a third pathway initiated by sub-terminal oxidation at the third carbon atom of Pristane. Novel intermediates detected suggest simultaneous sub-terminal and di-terminal oxidation pathways. © 2008 Elsevier Ltd. All rights reserved.

Nan Shen - One of the best experts on this subject based on the ideXlab platform.

  • 333 in vivo therapeutic success of microrna 155 mir 155 antagomir in a mouse model of lupus alveolar haemorrhage
    Lupus science & medicine, 2017
    Co-Authors: Y Wang, Shiyu Zhou, Nan Shen
    Abstract:

    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.

  • in vivo silencing of microrna 155 mir 155 ameliorated pulmonary hemorrhage induced by Pristane ba12p 100 ba12p 100
    Journal of Immunology, 2014
    Co-Authors: Shiyu Zhou, Xinfang Huang, Nan Shen, Dong Liang, John B Harley
    Abstract:

    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.

Shiyu Zhou - One of the best experts on this subject based on the ideXlab platform.

  • 333 in vivo therapeutic success of microrna 155 mir 155 antagomir in a mouse model of lupus alveolar haemorrhage
    Lupus science & medicine, 2017
    Co-Authors: Y Wang, Shiyu Zhou, Nan Shen
    Abstract:

    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.

  • in vivo therapeutic success of microrna 155 antagomir in a mouse model of lupus alveolar hemorrhage
    Arthritis & Rheumatism, 2016
    Co-Authors: Shiyu Zhou, Y Wang, Yao Meng, Chunyuan Xiao, Philip Brohawn, Brandon W Higgs, Bahija Jallal, Bo Qu, Xinfang Huang, Yuanjia Tang
    Abstract:

    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.

  • in vivo silencing of microrna 155 mir 155 ameliorated pulmonary hemorrhage induced by Pristane ba12p 100 ba12p 100
    Journal of Immunology, 2014
    Co-Authors: Shiyu Zhou, Xinfang Huang, Nan Shen, Dong Liang, John B Harley
    Abstract:

    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.