nad a22 4500 569303486 20190726063010.0 cr unu---uuuuu 190726e20190627xx s 000 0 eng 10.5167/uzh-171771 doi 10.1038/s41467-019-10859-w doi (ZORA)oai:www.zora.uzh.ch:171771 570 ddc 610 ddc Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M [Elektronische Daten] [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] openAccess eu-repo 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. Institute of Anatomy zora Cancer Research Center (CRC) zora General Biochemistry, Genetics and Molecular Biology, General Physics and Astronomy, General Chemistry zora Abe Hajime joint author Takeda Norihiko joint author Isagawa Takayuki joint author Semba Hiroaki joint author Nishimura Satoshi joint author Morioka Masaki Suimye joint author Nakagama Yu joint author Sato Tatsuyuki joint author Soma Katsura joint author Koyama Katsuhiro joint author Wake Masaki joint author Katoh Manami joint author Asagiri Masataka joint author Neugent Michael L. joint author Kim Jung-whan joint author Stockmann Christian joint author Yonezawa Tomo joint author Inuzuka Ryo joint author Hirota Yasushi joint author Maemura Koji joint author Yamashita Takeshi joint author Otsu Kinya joint author Manabe Ichiro joint author Nagai Ryozo joint author Komuro Issei joint author Nature Communications 10(1):2824 https://www.zora.uzh.ch/id/eprint/171771/1/41467_2019_Article_10859.pdf text/html WWW-Backlink auf das Repository 1 Journal Article PeerReviewed zora ZORA 856 40 https://www.zora.uzh.ch/id/eprint/171771/1/41467_2019_Article_10859.pdf text/html WWW-Backlink auf das Repository ZORA 700 1- Abe Hajime joint author ZORA 700 1- Takeda Norihiko joint author ZORA 700 1- Isagawa Takayuki joint author ZORA 700 1- Semba Hiroaki joint author ZORA 700 1- Nishimura Satoshi joint author ZORA 700 1- Morioka Masaki Suimye joint author ZORA 700 1- Nakagama Yu joint author ZORA 700 1- Sato Tatsuyuki joint author ZORA 700 1- Soma Katsura joint author ZORA 700 1- Koyama Katsuhiro joint author ZORA 700 1- Wake Masaki joint author ZORA 700 1- Katoh Manami joint author ZORA 700 1- Asagiri Masataka joint author ZORA 700 1- Neugent Michael L. joint author ZORA 700 1- Kim Jung-whan joint author ZORA 700 1- Stockmann Christian joint author ZORA 700 1- Yonezawa Tomo joint author ZORA 700 1- Inuzuka Ryo joint author ZORA 700 1- Hirota Yasushi joint author ZORA 700 1- Maemura Koji joint author ZORA 700 1- Yamashita Takeshi joint author ZORA 700 1- Otsu Kinya joint author ZORA 700 1- Manabe Ichiro joint author ZORA 700 1- Nagai Ryozo joint author ZORA 700 1- Komuro Issei joint author ZORA 773 0- Nature Communications 10(1):2824 BK010053 XK010053 XK010000 ZORA ZORA ZORA Journal Article openAccess