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Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M.
- Source :
-
Nature communications [Nat Commun] 2019 Jun 27; Vol. 10 (1), pp. 2824. Date of Electronic Publication: 2019 Jun 27. - Publication Year :
- 2019
-
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 <superscript>hi</superscript> 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.
- Subjects :
- Animals
Antigens, Ly genetics
Antigens, Ly metabolism
Female
Fibroblasts metabolism
Fibrosis genetics
Fibrosis pathology
Hypoxia genetics
Hypoxia pathology
Hypoxia-Inducible Factor 1, alpha Subunit genetics
Hypoxia-Inducible Factor 1, alpha Subunit metabolism
Male
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 genetics
Mitogen-Activated Protein Kinase 1 metabolism
Mitogen-Activated Protein Kinase 3 genetics
Mitogen-Activated Protein Kinase 3 metabolism
Oncostatin M genetics
Phosphorylation
Signal Transduction
Smad Proteins genetics
Smad Proteins metabolism
Transforming Growth Factor beta1 metabolism
Fibrosis metabolism
Hypoxia metabolism
Macrophages metabolism
Oncostatin M metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 10
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 31249305
- Full Text :
- https://doi.org/10.1038/s41467-019-10859-w