Macrophage hypoxia signaling regulates cardiac fibrosis via Oncostatin M

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.

Cells and gene expression programs in the adult human heart

“…Three additional subpopulations (FB2_ECMorg, FB3_activated, FB4_profibrotic Figure D1B, Supplementary Table D2 ) 59 , 60 . As macrophage secretion of oncostatin M, the OSMR and IL6ST ligand, would suppress cardiac fibrosis 61 , the distinctive gene programs of FB subpopulations are likely to govern stress-responsive cardiac remodeling. FB5_stromal expressed multiple stromal markers, including CD36 , EGFLAM and FLT1 .…”

“…In contrast, FB4_profibrotic had lower expression levels of ECM proteins but higher expression of cytokine receptors ( OSMR, IL6ST) , transcription factors ( JUNB , EGR1 , JUN , and HIF1A) and other genes in the OSM pathway ( SupplementaryFigure D1B,Supplementary Table D2)59 , 60 . As macrophage secretion of oncostatin M, the OSMR and IL6ST ligand, would suppress cardiac fibrosis61 , the distinctive gene programs of FB subpopulations are likely to govern stress-responsive cardiac remodeling. FB5_stromal expressed multiple stromal markers, including CD36 , EGFLAM and FLT1 .…”

Basic Biology of Hypoxic Responses Mediated by the Transcription Factor HIFs and Its Implication for Medicine

“…Takeda and a colleague established a mouse cardiac fibrosis and remodeling model induced by narrowing the transverse aorta. They found that myocardial tissue was hypoxic and that there was an accumulation of macrophages in the hypoxic regions of the heart, by examination via a phosphorescent probe as well as an analysis based on flow cytometry [189,190]. Furthermore, by analyzing mice with suppressed HIF-1α signaling of macrophages, they found that HIF-1α signaling induced macrophage accumulation in the heart [191].…”

BRD4 Inhibition by AZD5153 Promotes Antitumor Immunity via Depolarizing M2 Macrophages

“…Several TFs have been demonstrated to be involved in modulating the M2 phenotype of macrophages, such as PRDM1, MAF, STAT6, STAT3, HIF-1α, and C/EBPβ (10,(29)(30)(31)(32)(33). We assumed that AZD5153 epigenetically regulated the macrophage phenotype via alternating the expression levels of pivotal TFs.…”