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; Issei Komuro

doi:10.1038/s41467-019-10859-w

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, Issei Komuro

^*Corresponding author for this work

The University of Tokyo
Japan Science and Technology Agency
Nagasaki University
The Cardiovascular Institute
Jichi Medical University
Tokyo Medical and Dental University
Nagoya City University
University of Texas at Dallas
University of Zürich
Cancer Research Center Zurich
Chiba University

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

120 Citations (Scopus)

316 Downloads (Pure)

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, Ly6C^hi 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.

Original language	English
Article number	2824
Journal	Nature Communications
Volume	10
Issue number	1
Early online date	27 Jun 2019
DOIs	https://doi.org/10.1038/s41467-019-10859-w
Publication status	E-pub ahead of print - 27 Jun 2019

Access to Document

10.1038/s41467-019-10859-w

Macrophage hypoxia signaling regulates_ABE_Accepted5June2019Publishedonline27June2019_GOLD VoR (CC BY)Final published version, 1.1 MBLicence: CC BY

Cite this

Abe, H., Takeda, N., Isagawa, T., Semba, H., Nishimura, S., Morioka, M. S., Nakagama, Y., Sato, T., Soma, K., Koyama, K., Wake, M., Katoh, M., Asagiri, M., Neugent, M. L., Kim, J. W., Stockmann, C., Yonezawa, T., Inuzuka, R., Hirota, Y., ... Komuro, I. (2019). Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nature Communications, 10(1), Article 2824. Advance online publication. https://doi.org/10.1038/s41467-019-10859-w

@article{15185277accf47ca965a6efeee825c40,

title = "Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M",

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.",

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

year = "2019",

month = jun,

day = "27",

doi = "10.1038/s41467-019-10859-w",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Abe, H, Takeda, N, Isagawa, T, Semba, H, Nishimura, S, Morioka, MS, Nakagama, Y, Sato, T, Soma, K, Koyama, K, Wake, M, Katoh, M, Asagiri, M, Neugent, ML, Kim, JW, Stockmann, C, Yonezawa, T, Inuzuka, R, Hirota, Y, Maemura, K, Yamashita, T, Otsu, K, Manabe, I, Nagai, R & Komuro, I 2019, 'Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M', Nature Communications, vol. 10, no. 1, 2824. https://doi.org/10.1038/s41467-019-10859-w

TY - JOUR

T1 - Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M

AU - Abe, Hajime

AU - Takeda, Norihiko

AU - Isagawa, Takayuki

AU - Semba, Hiroaki

AU - Nishimura, Satoshi

AU - Morioka, Masaki Suimye

AU - Nakagama, Yu

AU - Sato, Tatsuyuki

AU - Soma, Katsura

AU - Koyama, Katsuhiro

AU - Wake, Masaki

AU - Katoh, Manami

AU - Asagiri, Masataka

AU - Neugent, Michael L.

AU - Kim, Jung whan

AU - Stockmann, Christian

AU - Yonezawa, Tomo

AU - Inuzuka, Ryo

AU - Hirota, Yasushi

AU - Maemura, Koji

AU - Yamashita, Takeshi

AU - Otsu, Kinya

AU - Manabe, Ichiro

AU - Nagai, Ryozo

AU - Komuro, Issei

PY - 2019/6/27

Y1 - 2019/6/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85068050473

U2 - 10.1038/s41467-019-10859-w

DO - 10.1038/s41467-019-10859-w

M3 - Article

AN - SCOPUS:85068050473

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2824

ER -

Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M

Abstract

Access to Document

Other files and links

Fingerprint

Cite this