The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis

Mariola Kurowska-Stolarska; Manhl K Hasoo; David J Welsh; Lynn Stewart; Donna McIntyre; Brian E Morton; Steven Johnstone; Ashley M Miller; Darren L Asquith; Neal L Millar; Ann B Millar; Carol A Feghali-Bostwick; Nikhil Hirani; Peter J Crick; Yuqin Wang; William J Griffiths; Iain B McInnes; Charles McSharry

doi:10.1016/j.jaci.2016.09.021

The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis

Mariola Kurowska-Stolarska, Manhl K Hasoo, David J Welsh, Lynn Stewart, Donna McIntyre, Brian E Morton, Steven Johnstone, Ashley M Miller, Darren L Asquith, Neal L Millar, Ann B Millar, Carol A Feghali-Bostwick, Nikhil Hirani, Peter J Crick, Yuqin Wang, William J Griffiths, Iain B McInnes, Charles McSharry

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways.

OBJECTIVES: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis.

METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155(-/-) mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors.

RESULTS: miR-155(-/-) mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155(-/-) fibroblasts.

CONCLUSION: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.

Original language	English
Journal	Journal of Allergy and Clinical Immunology
DOIs	https://doi.org/10.1016/j.jaci.2016.09.021
Publication status	Published - 14 Oct 2016

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10.1016/j.jaci.2016.09.021

1-s2.0-S0091674916311320-mainFinal published version, 2.19 MBLicence: Creative Commons: Attribution (CC-BY)

Nikhil Hirani
- n.hiranied.acuk
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Kurowska-Stolarska, M., Hasoo, M. K., Welsh, D. J., Stewart, L., McIntyre, D., Morton, B. E., Johnstone, S., Miller, A. M., Asquith, D. L., Millar, N. L., Millar, A. B., Feghali-Bostwick, C. A., Hirani, N., Crick, P. J., Wang, Y., Griffiths, W. J., McInnes, I. B., & McSharry, C. (2016). The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis. Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.09.021

@article{9749bd4804304833a6da49e560bc3309,

title = "The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis",

abstract = "BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways.OBJECTIVES: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis.METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155(-/-) mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors.RESULTS: miR-155(-/-) mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155(-/-) fibroblasts.CONCLUSION: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.",

author = "Mariola Kurowska-Stolarska and Hasoo, {Manhl K} and Welsh, {David J} and Lynn Stewart and Donna McIntyre and Morton, {Brian E} and Steven Johnstone and Miller, {Ashley M} and Asquith, {Darren L} and Millar, {Neal L} and Millar, {Ann B} and Feghali-Bostwick, {Carol A} and Nikhil Hirani and Crick, {Peter J} and Yuqin Wang and Griffiths, {William J} and McInnes, {Iain B} and Charles McSharry",

note = "Copyright {\textcopyright} 2016. Published by Elsevier Inc.",

year = "2016",

month = oct,

day = "14",

doi = "10.1016/j.jaci.2016.09.021",

language = "English",

journal = "Journal of Allergy and Clinical Immunology",

issn = "0091-6749",

publisher = "Mosby ",

}

Kurowska-Stolarska, M, Hasoo, MK, Welsh, DJ, Stewart, L, McIntyre, D, Morton, BE, Johnstone, S, Miller, AM, Asquith, DL, Millar, NL, Millar, AB, Feghali-Bostwick, CA, Hirani, N, Crick, PJ, Wang, Y, Griffiths, WJ, McInnes, IB & McSharry, C 2016, 'The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2016.09.021

TY - JOUR

T1 - The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis

AU - Kurowska-Stolarska, Mariola

AU - Hasoo, Manhl K

AU - Welsh, David J

AU - Stewart, Lynn

AU - McIntyre, Donna

AU - Morton, Brian E

AU - Johnstone, Steven

AU - Miller, Ashley M

AU - Asquith, Darren L

AU - Millar, Neal L

AU - Millar, Ann B

AU - Feghali-Bostwick, Carol A

AU - Hirani, Nikhil

AU - Crick, Peter J

AU - Wang, Yuqin

AU - Griffiths, William J

AU - McInnes, Iain B

AU - McSharry, Charles

PY - 2016/10/14

Y1 - 2016/10/14

N2 - BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways.OBJECTIVES: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis.METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155(-/-) mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors.RESULTS: miR-155(-/-) mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155(-/-) fibroblasts.CONCLUSION: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.

AB - BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways.OBJECTIVES: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis.METHODS: Bleomycin-induced lung fibrosis in wild-type and miR-155(-/-) mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors.RESULTS: miR-155(-/-) mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155(-/-) fibroblasts.CONCLUSION: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF.

U2 - 10.1016/j.jaci.2016.09.021

DO - 10.1016/j.jaci.2016.09.021

M3 - Article

C2 - 27746237

SN - 0091-6749

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

ER -

The role of microRNA-155/LXR pathway in experimental and Idiopathic Pulmonary Fibrosis

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