Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M

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 and Issei Komuro
Additional contact information
Hajime Abe: The University of Tokyo
Norihiko Takeda: The University of Tokyo
Takayuki Isagawa: Nagasaki University
Hiroaki Semba: The University of Tokyo
Satoshi Nishimura: PRESTO, JST
Masaki Suimye Morioka: Tokyo Medical and Dental University
Yu Nakagama: The University of Tokyo
Tatsuyuki Sato: The University of Tokyo
Katsura Soma: The University of Tokyo
Katsuhiro Koyama: The University of Tokyo
Masaki Wake: The University of Tokyo
Manami Katoh: The University of Tokyo
Masataka Asagiri: Nagoya City University
Michael L. Neugent: The University of Texas at Dallas
Jung-whan Kim: The University of Texas at Dallas
Christian Stockmann: University of Zurich
Tomo Yonezawa: Nagasaki University, Graduate School of Biomedical Sciences
Ryo Inuzuka: The University of Tokyo
Yasushi Hirota: The University of Tokyo
Koji Maemura: Nagasaki University
Takeshi Yamashita: The Cardiovascular Institute
Kinya Otsu: King’s College London British Heart Foundation Centre of Excellence
Ichiro Manabe: Chiba University
Ryozo Nagai: Jichi Medical University
Issei Komuro: The University of Tokyo

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10859-w

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