| First Author | Abe H | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 2824 |
| PubMed ID | 31249305 | Mgi Jnum | J:280252 |
| Mgi Id | MGI:6323823 | Doi | 10.1038/s41467-019-10859-w |
| Citation | Abe H, et al. (2019) Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M. Nat Commun 10(1):2824 |
| abstractText | 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-beta1) activates pro-fibrogenic mechanisms have been extensively studied and are recognized critical during fibrosis development, the factors regulating TGF-beta1 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)-1alpha 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-1alpha target gene, which directly inhibits the TGF-beta1 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. |
