THE CRITICAL ROLE OF THE HISTONE MODIFICATION ENZYME SETDB2 IN THE PATHOGENESIS OF ACUTE RESPIRATORY DISTRESS SYNDROME

ABSTRACT Introduction: Acute respiratory distress syndrome (ARDS) is a severe hypoxemic respiratory failure with a high in-hospital mortality. However, the molecular mechanisms underlying ARDS remain unclear. Recent findings have indicated that the onset of severe inflammatory diseases, such as sepsis, is regulated by epigenetic changes. We investigated the role of epigenetic changes in ARDS pathogenesis using mouse models and human samples. Methods: Acute respiratory distress syndrome was induced in a mouse model (C57BL/6 mice, myeloid cell or vascular endothelial cell [VEC]–specific SET domain bifurcated 2 [Setdb2]–deficient mice [Setdb2ffLyz2Cre+ or Setdb2ffTie2Cre+], and Cre− littermates) by intratracheal administration of lipopolysaccharide (LPS). Analyses were performed at 6 and 72 h after LPS administration. Sera and lung autopsy specimens from ARDS patients were examined. Results: In the murine ARDS model, we observed high expression of the histone modification enzyme SET domain bifurcated 2 (Setdb2) in the lungs. In situ hybridization examination of the lungs revealed Setdb2 expression in macrophages and VECs. The histological score and albumin level of bronchoalveolar lavage fluid were significantly increased in Setdb2ffTie2Cre+ mice following LPS administration compared with Setdb2ffTie2Cre- mice, whereas there was no significant difference between the control and Setdb2ffLyz2Cre+ mice. Apoptosis of VECs was enhanced in Setdb2ffTie2Cre+ mice. Among the 84 apoptosis-related genes, the expression of TNF receptor superfamily member 10b (Tnfrsf10b) was significantly higher in Setdb2ffTie2Cre+ mice than in control mice. Acute respiratory distress syndrome patients' serum showed higher SETDB2 levels than those of healthy volunteers. SETDB2 levels were negatively correlated with the partial pressure of oxygen in arterial blood/fraction of inspiratory oxygen concentration ratio. Conclusion: Acute respiratory distress syndrome elevates Setdb2, apoptosis of VECs, and vascular permeability. Elevation of histone methyltransferase Setdb2 suggests the possibility to histone change and epigenetic modification. Thus, Setdb2 may be a novel therapeutic target for controlling the pathogenesis of ARDS.

[1]  Katherine A. Gallagher,et al.  Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2 , 2021, Proceedings of the National Academy of Sciences.

[2]  T. Diekwisch,et al.  Histone Methylation: Achilles Heel and Powerful Mediator of Periodontal Homeostasis , 2020, Journal of dental research.

[3]  F. Martinez,et al.  Severe Covid-19. , 2020, The New England journal of medicine.

[4]  Xu Li,et al.  Acute respiratory failure in COVID-19: is it “typical” ARDS? , 2020, Critical Care.

[5]  Q. Ye,et al.  The pathogenesis and treatment of the `Cytokine Storm' in COVID-19 , 2020, Journal of Infection.

[6]  M. Inomata,et al.  Role of increased vascular permeability in chemotherapy‐induced alopecia: In vivo imaging of the hair follicular microenvironment in mice , 2020, Cancer science.

[7]  C. Burant,et al.  The Histone Methyltransferase Setdb2 Modulates Macrophage Phenotype and Uric Acid Production in Diabetic Wound Repair. , 2019, Immunity.

[8]  M. Matthay,et al.  Pathogenesis of Acute Respiratory Distress Syndrome , 2019, Seminars in Respiratory and Critical Care Medicine.

[9]  Toshihiro Ito,et al.  Abrogated Caveolin-1 expression via histone modification enzyme Setdb2 regulates brain edema in a mouse model of influenza-associated encephalopathy , 2019, Scientific Reports.

[10]  Yury B. Porozov,et al.  TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis , 2017, Vaccines.

[11]  Yutong Zhao,et al.  Regulation of the ubiquitylation and deubiquitylation of CREB-binding protein modulates histone acetylation and lung inflammation , 2017, Science Signaling.

[12]  Lefeng Wang,et al.  Inhibition of Murine Pulmonary Microvascular Endothelial Cell Apoptosis Promotes Recovery of Barrier Function under Septic Conditions , 2017, Mediators of inflammation.

[13]  R. Taneja,et al.  A drive in SUVs: From development to disease , 2017, Epigenetics.

[14]  I. Manabe,et al.  The H3K9 methyltransferase Setdb1 regulates TLR4-mediated inflammatory responses in macrophages , 2016, Scientific Reports.

[15]  M. Balaan,et al.  Acute Respiratory Distress Syndrome , 2016, Critical care nursing quarterly.

[16]  Toshihiro Ito,et al.  Type I Interferon Induced Epigenetic Regulation of Macrophages Suppresses Innate and Adaptive Immunity in Acute Respiratory Viral Infection , 2015, PLoS pathogens.

[17]  S. Gill,et al.  Role of pulmonary microvascular endothelial cell apoptosis in murine sepsis-induced lung injury in vivo , 2015, Respiratory Research.

[18]  V. Litvak,et al.  The methyltransferase Setdb2 mediates virus-induced susceptibility to bacterial superinfection , 2014, Nature Immunology.

[19]  A. Yoshimura,et al.  Spred-2 Deficiency Exacerbates Lipopolysaccharide-Induced Acute Lung Inflammation in Mice , 2014, PloS one.

[20]  M. Crow,et al.  Mitogen-activated protein kinase-activated protein kinase 2 mediates apoptosis during lung vascular permeability by regulating movement of cleaved caspase 3. , 2014, American journal of respiratory cell and molecular biology.

[21]  S. Gill,et al.  Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. , 2012, American journal of respiratory cell and molecular biology.

[22]  J. Ghiso,et al.  TRAIL death receptors DR4 and DR5 mediate cerebral microvascular endothelial cell apoptosis induced by oligomeric Alzheimer's Aβ , 2012, Cell Death and Disease.

[23]  Rosette Lidereau,et al.  Similar NF-κB Gene Signatures in TNF-α Treated Human Endothelial Cells and Breast Tumor Biopsies , 2011, PloS one.

[24]  D. Dean,et al.  Gene therapy for ALI/ARDS. , 2011, Critical care clinics.

[25]  C. Bai,et al.  The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine , 2010, Expert review of respiratory medicine.

[26]  Y. Dou,et al.  Impaired CD4+ T‐cell proliferation and effector function correlates with repressive histone methylation events in a mouse model of severe sepsis , 2010, European journal of immunology.

[27]  Ruslan Medzhitov,et al.  Transcriptional control of the inflammatory response , 2009, Nature Reviews Immunology.

[28]  K. Eguchi,et al.  IFN-gamma/JAK/STAT pathway-induced inhibition of DR4 and DR5 expression on endothelial cells is cancelled by cycloheximide-sensitive mechanism: novel finding of cycloheximide-regulating death receptor expression. , 2005, International journal of molecular medicine.

[29]  G. Filippatos,et al.  Apoptosis in lung injury and remodeling. , 2004, Journal of applied physiology.

[30]  H. Hollema,et al.  Tissue Distribution of the Death Ligand TRAIL and Its Receptors , 2004, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[31]  S. Akira,et al.  TRAM is specifically involved in the Toll-like receptor 4–mediated MyD88-independent signaling pathway , 2003, Nature Immunology.

[32]  L. Hood,et al.  Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway. , 1997, Immunity.

[33]  Q. Lu,et al.  Pulmonary Endothelial Cell Apoptosis in Emphysema and Acute Lung Injury. , 2018, Advances in anatomy, embryology, and cell biology.

[34]  Arthur S Slutsky,et al.  Acute Respiratory Distress Syndrome The Berlin Definition , 2012 .

[35]  C. Chung,et al.  Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge. , 2006, American journal of physiology. Lung cellular and molecular physiology.