Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M

• DOI: 10.1038/s41467-019-10859-w
• Publication Date: 2019-06-27T10:02:45Z
• Authors: Hajime Abe; Norihiko Takeda; Takayuki Isagawa; Hiroaki Semba; Satoshi Nishimura; Masaki Suimye Mor...; 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
• Keywords: Oncostatin M; Cardiac Fibrosis; Hypoxia-Inducible Factors; Hypoxia

Abstract The fibrogenic response in tissue-resident fibroblasts is determined by the balance between activation and repression signals from tissue microenvironment. While molecular pathways which transforming growth factor-1 (TGF-β1) activates pro-fibrogenic mechanisms have been extensively studied are recognized critical during fibrosis development, factors regulating TGF-β1 signaling poorly understood. Here we show that macrophage hypoxia suppresses excessive a heart via oncostatin-m (OSM) secretion. During cardiac remodeling, Ly6C hi monocytes/macrophages accumulate hypoxic areas through hypoxia-inducible factor (HIF)-1α dependent manner fibroblast activation. As an underlying mechanism, identify OSM, part of interleukin 6 cytokine family, as HIF-1α target gene, directly inhibits mediated extracellular signal-regulated kinase 1/2-dependent phosphorylation SMAD linker region. These results demonstrate regulates OSM secretion vivo.