The transcriptional control of the VEGFA-VEGFR1 (FLT1) axis in alternatively polarized murine and human macrophages

Frontiers in Immunology

Immunology

Gergely Nagy¹  Karoly Jambrovics¹  Beata Scholtz¹  Krisztian P. Bene¹  Laszlo Nagy²  Apolka Domokos³  Noemí Caballero-Sánchez³  Zsofia Varga⁴  Zsolt Czimmerer⁵  Anett Mazlo⁶  Attila Bacsi⁷  Laszlo Halasz⁸  Eszter Varadi⁹  Gabor J. Szebeni^1,10  Eniko Szabo^1,10  Viktoria Jeney^1,11 

[1]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[2]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[3]Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States

[4]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[5]Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, Debrecen, Hungary

[6]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[7]Institute of Genetics, Biological Research Centre, Eotvos Lorand Research Network, Szeged, Hungary

[8]Department of Biochemistry and Molecular Biology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[9]Institute of Genetics, Biological Research Centre, Eotvos Lorand Research Network, Szeged, Hungary

[10]Department of Immunology, Albert Szent-Györgyi Medical School, Faculty of Science and Informatics, University of Szeged, Szeged, Hungary

[11]Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[12]Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

[13]ELKH-DE Allergology Research Group, Debrecen, Hungary

[14]Departments of Medicine and Biological Chemistry, Johns Hopkins University School of Medicine, Institute for Fundamental Biomedical Research, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United States

[15]Institute of Genetics, Biological Research Centre, Eotvos Lorand Research Network, Szeged, Hungary

[16]Doctoral School in Biology, University of Szeged, Szeged, Hungary

[17]Laboratory of Functional Genomics, Biological Research Centre Eotvos Lorand Research Network, Szeged, Hungary

[18]MTA-DE Lendület Vascular Pathophysiology Research Group, Research Centre for Molecular Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

关键词: macrophage;    IL-4;    VEGFA;    FLT1;    hypoxia;    transcriptional regulation;    STAT6;    EGR2;   

DOI  :  10.3389/fimmu.2023.1168635

 received in 2023-02-17, accepted in 2023-04-11,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionMacrophages significantly contribute to the regulation of vessel formation under physiological and pathological conditions. Although the angiogenesis-regulating role of alternatively polarized macrophages is quite controversial, a growing number of evidence shows that they can participate in the later phases of angiogenesis, including vessel sprouting and remodeling or regression. However, the epigenetic and transcriptional regulatory mechanisms controlling this angiogenesis-modulating program are not fully understood.ResultsHere we show that IL-4 can coordinately regulate the VEGFA-VEGFR1 (FLT1) axis via simultaneously inhibiting the proangiogenic Vegfa and inducing the antiangiogenic Flt1 expression in murine bone marrow-derived macrophages, which leads to the attenuated proangiogenic activity of alternatively polarized macrophages. The IL-4-activated STAT6 and IL-4-STAT6 signaling pathway-induced EGR2 transcription factors play a direct role in the transcriptional regulation of the Vegfa-Flt1 axis. We demonstrated that this phenomenon is not restricted to the murine bone marrow-derived macrophages, but can also be observed in different murine tissue-resident macrophages ex vivo and parasites-elicited macrophages in vivo with minor cell type-specific differences. Furthermore, IL-4 exposure can modulate the hypoxic response of genes in both murine and human macrophages leading to a blunted Vegfa/VEGFA and synergistically induced Flt1/FLT1 expression.DiscussionOur findings establish that the IL-4-activated epigenetic and transcriptional program can determine angiogenesis-regulating properties in alternatively polarized macrophages under normoxic and hypoxic conditions.

【 授权许可】

Unknown   
Copyright © 2023 Domokos, Varga, Jambrovics, Caballero-Sánchez, Szabo, Nagy, Scholtz, Halasz, Varadi, Bene, Mazlo, Bacsi, Jeney, Szebeni, Nagy and Czimmerer