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The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma

Katsunari Makino, Masatoshi Jinnin, Ayaka Hirano, Keitaro Yamane, Mitsuhiko Eto, Takamitsu Kusano, Noritoshi Honda, Ikko Kajihara, Takamitsu Makino, Keisuke Sakai, Shinichi Masuguchi, Satoshi Fukushima and Hironobu Ihn
J Immunol March 15, 2013, 1200822; DOI: https://doi.org/10.4049/jimmunol.1200822
Katsunari Makino
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Masatoshi Jinnin
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Ayaka Hirano
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Keitaro Yamane
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Mitsuhiko Eto
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Takamitsu Kusano
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Noritoshi Honda
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Ikko Kajihara
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Takamitsu Makino
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Keisuke Sakai
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Shinichi Masuguchi
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Satoshi Fukushima
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Hironobu Ihn
Department of Dermatology and Plastic Surgery, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
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Abstract

Systemic and localized scleroderma (SSc and LSc) is characterized by excessive deposition of collagen and tissue fibrosis in the skin. Although they have fundamental common characteristics including autoimmunity, little is known about the exact mechanism that mediates the excessive collagen expression in these disorders. In the current study, we tried to evaluate the possibility that microRNAs (miRNAs) play some roles in the pathogenesis of fibrosis seen in these diseases. miRNA expression patterns were evaluated by miRNA array analysis, real-time PCR, and in situ hybridization. The function of miRNAs in dermal fibroblasts was assessed using miRNA inhibitors, precursors, or protectors. In the mouse model of bleomycin-induced dermal sclerosis, the overexpression of miRNAs was performed by i.p. miRNA injection. We demonstrated let-7a expression was downregulated in SSc and LSc skin both in vivo and in vitro, compared with normal or keloid skin. The inhibition or overexpression of let-7a in human or mouse skin fibroblasts affected the protein expression of type I collagen or luciferase activity of collagen 3′-untranslated region. Also, we found let-7a was detectable and quantitative in the serum and investigated serum let-7a levels in patients with SSc or LSc. let-7a concentration was significantly decreased in these patients, especially in LSc patients. Moreover, we revealed that the intermittent overexpression of let-7a in the skin by i.p. miRNA injection improved the skin fibrosis induced by bleomycin in mice. Investigation of more detailed mechanisms of miRNA-mediated regulation of collagen expression may lead to new therapeutic approaches against SSc and LSc.

Footnotes

  • This work was supported in part by a grant for scientific research from the Japanese Ministry of Education, Science, Sports, and Culture, by project research on intractable diseases from the Japanese Ministry of Health, Labor, and Welfare, and by a research grant from Shiseido.

  • The sequences presented in this article have been submitted to the Gene Expression Omnibus microarray data repository (http://www.ncbi.nlm.nih.gov/geo/) under accession number GSE43469.

  • Received March 14, 2012.
  • Accepted February 13, 2013.
  • Copyright © 2013 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (5)
The Journal of Immunology
Vol. 206, Issue 5
1 Mar 2021
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The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma
Katsunari Makino, Masatoshi Jinnin, Ayaka Hirano, Keitaro Yamane, Mitsuhiko Eto, Takamitsu Kusano, Noritoshi Honda, Ikko Kajihara, Takamitsu Makino, Keisuke Sakai, Shinichi Masuguchi, Satoshi Fukushima, Hironobu Ihn
The Journal of Immunology March 15, 2013, 1200822; DOI: 10.4049/jimmunol.1200822

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The Downregulation of microRNA let-7a Contributes to the Excessive Expression of Type I Collagen in Systemic and Localized Scleroderma
Katsunari Makino, Masatoshi Jinnin, Ayaka Hirano, Keitaro Yamane, Mitsuhiko Eto, Takamitsu Kusano, Noritoshi Honda, Ikko Kajihara, Takamitsu Makino, Keisuke Sakai, Shinichi Masuguchi, Satoshi Fukushima, Hironobu Ihn
The Journal of Immunology March 15, 2013, 1200822; DOI: 10.4049/jimmunol.1200822
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Print ISSN 0022-1767        Online ISSN 1550-6606