In Vivo Therapeutic Success of MicroRNA‐155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage

Zhou, Shuhua; Wang, Yan; Meng, Yao; Xiao, Chunyuan; Liu, Zheng; Brohawn, Philip Z.; Higgs, Brandon W.; Jallal, Bahija; Qian, Juan; Qu, Bo; Huang, Xinfang; Tang, Yue; Yao, Yihong; Harley, John B.; Shen, Nan

doi:10.1002/art.39485

Cited by 65 publications

(44 citation statements)

References 46 publications

(54 reference statements)

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“…We extensively performed bioinformatics analysis and found that miR-155 has a seed region at the 3′UTR of PPARγ gene (www.microrna.org) (Supplementary Fig.1A). A very recent study identified PPARα, a direct target of miR-155 [20] and showed that miR-155 regulates inflammation via targeting PPARα after inducing diffuse alveolar hemorrhage. We found a decrease in PPARα mRNA after alcohol diet in WT mice and this decease was prevented in miR-155 KO mice (Fig.2A).…”

Section: Resultsmentioning

confidence: 99%

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala

Csák

Saha

et al. 2016

Journal of Hepatology

251

270

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Background & Aims Alcoholic liver disease (ALD) ranges from fatty liver to inflammation and cirrhosis. miRNA-155 is an important regulator of inflammation. In this study, we describe the in vivo role of miR-155 in ALD. Methods Wild type, WT (C57/BL6J) or miR-155 KO and TLR4 KO mice received Lieber-DeCarli diet for 5 weeks. Some mice received corn oil or CCl4 for 2 or 9 weeks. Results We found that miR-155 KO mice are protected from alcohol-induced steatosis and inflammation. The reduction in alcohol-induced fat accumulation in miR-155 KO mice was associated with increased PPRE and PPARα (miR-155 target) binding and decreased MCP1 production. Treatment with a miR-155 inhibitor increased PPARγ expression in naive and alcohol treated RAW macrophages. Alcohol increased lipid metabolism genes (FABP4, LXRα, ACC1 and LDLR) in WT mice and this was prevented in KO mice. Alcohol diet induced increase in the number of CD163+CD206+ infiltrating macrophages and neutrophils in WT was prevented in miR-155 KO mice. Kupffer cells isolated from miR-155 KO mice exhibited predominance of M2 phenotype when exposed to M1 polarized signals and this was due to increased C/EBPβ. Profibrotic genes were attenuated in miR-155 KO mice after alcohol diet or CCl4 treatment. Compared to WT attenuation in CCl4 induced hydroxyproline and α SMA was observed in KO mice. Finally, we show TLR4 signaling regulates miR-155 as TLR4 KO mice showed no induction of miR-155 after alcohol diet. Conclusions Collectively our results demonstrated the role of miR-155 in alcohol-induced steatohepatitis and fibrosis in vivo.

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Section: Resultsmentioning

confidence: 99%

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

Bala

Csák

Saha

et al. 2016

Journal of Hepatology

251

270

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“…MiR155, as a molecule potentially involved in lupus pathogenesis, might constitute an interesting therapeutic target [28]. …”

Section: Discussionmentioning

confidence: 99%

“…A recent publication could show that miR155 gene expression in lung tissue increased within 7 days after pristane injection as did genes encoding for toll-like receptor 4 (TLR-4), TLR-7 and TLR-2 and mitogen-activated protein kinase (MAPK) pathways that encode pro-inflammatory cytokines (e.g. TNF receptor factor 6 [TRAF6]) and genes related to the IL-6 and TNF signaling pathways [28]. In mir155-deficient mice, however, there was a reduced activation of the MAPK and TLR pathways upon stimulation with pristane and decreased levels of Il-6 and TNF [27, 28, 38].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus

et al. 2017

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ObjectiveWe herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus.Materials and methodsSystemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes.ResultsAfter induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15).ConclusionsMiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.

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“…Furthermore, it suppresses Bcl6, a transcription factor that counter-regulates activation of NF-κB, and induces expression of Ccl2 by macrophages [32]. Thus, it is considered to be a potential therapeutic target in a variety of inflammatory diseases including rheumatoid arthritis [33], although studies in animal experimental models have reported variable success to date [34][35][36].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

Chia

Kumar

Foster

et al. 2018

Int Arch Allergy Immunol

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Background: Allergic asthma is common in childhood and is associated with a T-helper type 2 (Th2)-biased immunological response. Exacerbations of asthma are characterised by increased inflammation of the airways, which appears to be driven by interleukin (IL)-33 that can activate pulmonary macrophages. The Th2 cytokine environment of allergic asthma may contribute to exaggerated airway inflammation. Objectives: To test this, we assessed whether production of pro-inflammatory cytokines by IL-33-stimulated macrophages was enhanced in cells pre-treated with the key Th2 cytokines IL-4 and IL-13. We also investigated whether this was associated with altered expression of regulatory microRNAs (miRNAs). Methods: RAW264.7 cells cultured with IL-4 and IL-13 for 48 h were stimulated with IL-33 for 4 h. Pro-inflammatory mediators were assessed using quantitative real-time PCR (RT-PCR). Expression of miRNAs was assessed using microarrays and RT-PCR. In further experiments, we examined whether resolvin E1 (RvE1), which promotes the resolution of experimental asthmatic inflammation in vivo, could suppress the enhanced response by treating cells with RvE1 concurrently with IL-33 stimulation. Results: In cells pre-treated with IL-4 and IL-13, expression of mRNA for Ccl3, Ccl5, Ccl17, Ccl24, and Il1b in response to IL-33 stimulation was significantly increased. This was paralleled by up-regulated expression of miR-155-5p, a miRNA that is predicted to regulate several aspects of allergic inflammation. RvE1 suppressed the enhanced production of Ccl3, Ccl5, Ccl24, and Il1b. Conclusions: We conclude that IL-33-activated macrophages may contribute to the exaggerated airway inflammation in exacerbations of allergic asthma, and that RvE1 has potential as a therapeutic agent that targets macrophages.

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In Vivo Therapeutic Success of MicroRNA‐155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage

Cited by 65 publications

References 46 publications

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

The pro-inflammatory effects of miR-155 promote liver fibrosis and alcohol-induced steatohepatitis

MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus

Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment

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