Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-06-27

AUTHORS

Hajime Abe, Norihiko Takeda, Takayuki Isagawa, Hiroaki Semba, Satoshi Nishimura, Masaki Suimye Morioka, Yu Nakagama, Tatsuyuki Sato, Katsura Soma, Katsuhiro Koyama, Masaki Wake, Manami Katoh, Masataka Asagiri, Michael L. Neugent, Jung-whan Kim, Christian Stockmann, Tomo Yonezawa, Ryo Inuzuka, Yasushi Hirota, Koji Maemura, Takeshi Yamashita, Kinya Otsu, Ichiro Manabe, Ryozo Nagai, Issei Komuro

ABSTRACT

The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from the tissue microenvironment. While the molecular pathways by which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-β1 signaling are poorly understood. Here we show that macrophage hypoxia signaling suppresses excessive fibrosis in a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6Chi monocytes/macrophages accumulate in hypoxic areas through a hypoxia-inducible factor (HIF)-1α dependent manner and suppresses cardiac fibroblast activation. As an underlying molecular mechanism, we identify OSM, part of the interleukin 6 cytokine family, as a HIF-1α target gene, which directly inhibits the TGF-β1 mediated activation of cardiac fibroblasts through extracellular signal-regulated kinase 1/2-dependent phosphorylation of the SMAD linker region. These results demonstrate that macrophage hypoxia signaling regulates fibroblast activation through OSM secretion in vivo. More... »

PAGES

2824

Journal

TITLE

Nature Communications

ISSUE

1

VOLUME

10

Author Affiliations

  • The School of Cardiovascular Medicine and Sciences, King’s College London British Heart Foundation Centre of Excellence, London, SE5 9NU UK
  • PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, 332-0012 Japan
  • Graduate School of Biomedical Science, Nagasaki University, 1-7-1sakamoto, Nagasaki, 852-8501 Japan
  • Department of Cardiovascular Medicine, The Cardiovascular Institute, 3-2-19 Nishiazabu, Minato-ku, Tokyo, 106-00031 Japan
  • Center for Molecular Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498 Japan
  • Depertment of Bioinformatics, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo, 113–8510 Japan
  • Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
  • Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
  • Department of Pathobiology, Graduate School of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabe-dori, Mizuho-ku, Nagoya, 467-8603 Japan
  • Department of Biological Sciences, The University of Texas at Dallas, 800W. Campbell Road FO 3.704G, Richardson, TX 75080 USA
  • Cancer Research Center Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland
  • Center for Therapeutic Innovation, Gene Research Center, Center for Frontier Life Sciences, Nagasaki University, Graduate School of Biomedical Sciences, 1-12-14 Sakamoto, Nagasaki, 852-8523 Japan
  • Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655 Japan
  • Department of Disease Biology and Molecular Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670 Japan
  • Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken, Tochigi, 329-0498 Japan
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/s41467-019-10859-w

    DOI

    http://dx.doi.org/10.1038/s41467-019-10859-w

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1117499684

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31249305


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