Macrophage hypoxia signaling suppresses excessive cardiac fibrosis during remodeling through the secretion of Oncostatin M, which directly inhibits TGF-β1-mediated fibroblast activation.
Does macrophage hypoxia signaling regulate cardiac fibrosis via Oncostatin M in preclinical models of cardiac remodeling?
Macrophage-derived Oncostatin M, induced by hypoxia via HIF-1α, acts as a critical negative regulator of cardiac fibrosis by inhibiting TGF-β1 signaling in fibroblasts.
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.
Abe et al. (Thu,) conducted a other in Cardiac fibrosis. Macrophage hypoxia signaling and Oncostatin M vs. Normoxia / Wild-type controls was evaluated on Cardiac fibrosis and fibroblast activation. Macrophage hypoxia signaling suppresses excessive cardiac fibrosis during remodeling through the secretion of Oncostatin M, which directly inhibits TGF-β1-mediated fibroblast activation.
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