Orphan Nuclear Receptor Family 4A (NR4A) Members NR4A2 and NR4A3 Selectively Modulate Elements of the Monocyte Response to Buffered Hypercapnia

被引:1
作者
Phelan, David E. [1 ,2 ]
Reddan, Ben [1 ,2 ]
Shigemura, Masahiko [3 ]
Sznajder, Jacob I. [4 ]
Crean, Daniel [2 ,5 ]
Cummins, Eoin P. [1 ,2 ]
机构
[1] Univ Coll Dublin, Sch Med, Dublin, Ireland
[2] Univ Coll Dublin, Conway Inst Biomol & Biomed Sci, Dublin, Ireland
[3] Northwestern Univ, Div Thorac Surg, Chicago, IL 60611 USA
[4] Northwestern Univ, Feinberg Sch Med, Pulm & Crit Care Med, Chicago, IL 60611 USA
[5] Univ Coll Dublin, Sch Vet Med, Dublin, Ireland
基金
爱尔兰科学基金会;
关键词
hypercapnia; carbon dioxide; CO2; orphan nuclear receptor family 4A; RNA-seq; transcription; DNA-BINDING; PROTEIN; EXPRESSION; LOCALIZATION; MACROPHAGES; INSIGHT; PATHWAY; TARGETS; ETS-1; RELB;
D O I
10.3390/ijms25052852
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypercapnia occurs when the partial pressure of carbon dioxide (CO2) in the blood exceeds 45 mmHg. Hypercapnia is associated with several lung pathologies and is transcriptionally linked to suppression of immune and inflammatory signalling through poorly understood mechanisms. Here we propose Orphan Nuclear Receptor Family 4A (NR4A) family members NR4A2 and NR4A3 as potential transcriptional regulators of the cellular response to hypercapnia in monocytes. Using a THP-1 monocyte model, we investigated the sensitivity of NR4A family members to CO2 and the impact of depleting NR4A2 and NR4A3 on the monocyte response to buffered hypercapnia (10% CO2) using RNA-sequencing. We observed that NR4A2 and NR4A3 are CO2-sensitive transcription factors and that depletion of NR4A2 and NR4A3 led to reduced CO2-sensitivity of mitochondrial and heat shock protein (Hsp)-related genes, respectively. Several CO2-sensitive genes were, however, refractory to depletion of NR4A2 and NR4A3, indicating that NR4As regulate certain elements of the cellular response to buffered hypercapnia but that other transcription factors also contribute. Bioinformatic analysis of conserved CO2-sensitive genes implicated several novel putative CO2-sensitive transcription factors, of which the ETS Proto-Oncogene 1 Transcription Factor (ETS-1) was validated to show increased nuclear expression in buffered hypercapnia. These data give significant insights into the understanding of immune responses in patients experiencing hypercapnia.
引用
收藏
页数:17
相关论文
共 51 条
  • [1] Identification of NR4A2 as a transcriptional activator of IL-8 expression in human inflammatory arthritis
    Aherne, Carol M.
    McMorrow, Jason
    Kane, David
    FitzGerald, Oliver
    Mix, Kimberlee S.
    Murphy, Evelyn P.
    [J]. MOLECULAR IMMUNOLOGY, 2009, 46 (16) : 3345 - 3357
  • [2] Carbon dioxide regulates cholesterol levels through SREBP2
    Bolshette, Nityanand
    Ezagouri, Saar
    Dandavate, Vaishnavi
    Karavaeva, Iuliia
    Golik, Marina
    Wang, Hu
    Espenshade, Peter J.
    Osborne, Timothy F.
    Han, Xianlin
    Asher, Gad
    [J]. PLOS BIOLOGY, 2023, 21 (11)
  • [3] Hypercapnia selectively modulates LPS-induced changes in innate immune and DNA replication-related gene transcription in the macrophage
    Casalino-Matsuda, S. Marina
    Berdnikovs, Sergejs
    Wang, Naizhen
    Nair, Aisha
    Gates, Khalilah L.
    Beitel, Greg J.
    Sporn, Peter H. S.
    [J]. INTERFACE FOCUS, 2021, 11 (02)
  • [4] Hypercapnia Inhibits Autophagy and Bacterial Killing in Human Macrophages by Increasing Expression of Bcl-2 and Bcl-xL
    Casalino-Matsuda, S. Marina
    Nair, Aisha
    Beitel, Greg J.
    Gates, Khalilah L.
    Sporn, Peter H. S.
    [J]. JOURNAL OF IMMUNOLOGY, 2015, 194 (11) : 5388 - 5396
  • [5] Targeting NR4A Nuclear Receptors to Control Stromal Cell Inflammation, Metabolism, Angiogenesis, and Tumorigenesis
    Crean, Daniel
    Murphy, Evelyn P.
    [J]. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2021, 9
  • [6] Adenosine Modulates NR4A Orphan Nuclear Receptors To Attenuate Hyperinflammatory Responses in Monocytic Cells
    Crean, Daniel
    Cummins, Eoin P.
    Bahar, Bojlul
    Mohan, Helen
    McMorrow, Jason P.
    Murphy, Evelyn P.
    [J]. JOURNAL OF IMMUNOLOGY, 2015, 195 (04) : 1436 - 1448
  • [7] MECHANISMS AND CONSEQUENCES OF OXYGEN AND CARBON DIOXIDE SENSING IN MAMMALS
    Cummins, Eoin P.
    Strowitzki, Moritz J.
    Taylor, Cormac T.
    [J]. PHYSIOLOGICAL REVIEWS, 2020, 100 (01) : 463 - 488
  • [8] TRAF2 Is a Novel Ubiquitin E3 Ligase for the Na,K-ATPase β-Subunit That Drives Alveolar Epithelial Dysfunction in Hypercapnia
    Gabrielli, Nieves M.
    Mazzocchi, Luciana C.
    Kryvenko, Vitalii
    Tello, Khodr
    Herold, Susanne
    Morty, Rory E.
    Grimminger, Friedrich
    Dada, Laura A.
    Seeger, Werner
    Sznajder, Jacob, I
    Vadasz, Istvan
    [J]. FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2021, 9
  • [9] Hypercapnia Impairs ENaC Cell Surface Stability by Promoting Phosphorylation, Polyubiquitination and Endocytosis of β-ENaC in a Human Alveolar Epithelial Cell Line
    Gwozdzinska, Paulina
    Buchbinder, Benno A.
    Mayer, Konstantin
    Herold, Susanne
    Morty, Rory E.
    Seeger, Werner
    Vadasz, Istvan
    [J]. FRONTIERS IN IMMUNOLOGY, 2017, 8
  • [10] Function of Nr4a Orphan Nuclear Receptors in Proliferation, Apoptosis and Fuel Utilization Across Tissues
    Herring, Jacob A.
    Elison, Weston S.
    Tessem, Jeffery S.
    [J]. CELLS, 2019, 8 (11)