Mesenchymal stromal cells-derived extracellular vesicles reprogramme macrophages in ARDS models through the miR-181a-5p-PTEN-pSTAT5-SOCS1 axis

Rationale A better understanding of the mechanism of action of mesenchymal stromal cells (MSCs) and their extracellular vesicles (EVs) is needed to support their use as novel therapies for acute respiratory distress syndrome (ARDS). Macrophages are important mediators of ARDS inflammatory response. Suppressor of cytokine signalling (SOCS) proteins are key regulators of the macrophage phenotype switch. We therefore investigated whether SOCS proteins are involved in mediation of the MSC effect on human macrophage reprogramming. Methods Human monocyte-derived macrophages (MDMs) were stimulated with lipopolysaccharide (LPS) or plasma samples from patients with ARDS (these samples were previously classified into hypo-inflammatory and hyper-inflammatory phenotype) and treated with MSC conditioned medium (CM) or EVs. Protein expression was measured by Western blot. EV micro RNA (miRNA) content was determined by miRNA sequencing. In vivo: LPS-injured C57BL/6 mice were given EVs isolated from MSCs in which miR-181a had been silenced by miRNA inhibitor or overexpressed using miRNA mimic. Results EVs were the key component of MSC CM responsible for anti-inflammatory modulation of human macrophages. EVs significantly reduced secretion of tumour necrosis factor-α and interleukin-8 by LPS-stimulated or ARDS plasma-stimulated MDMs and this was dependent on SOCS1. Transfer of miR-181a in EVs downregulated phosphatase and tensin homolog (PTEN) and subsequently activated phosphorylated signal transducer and activator of transcription 5 (pSTAT5) leading to upregulation of SOCS1 in macrophages. In vivo, EVs alleviated lung injury and upregulated pSTAT5 and SOCS1 expression in alveolar macrophages in a miR181-dependent manner. Overexpression of miR-181a in MSCs significantly enhanced therapeutic efficacy of EVs in this model. Conclusion miR-181a-PTEN-pSTAT5-SOCS1 axis is a novel pathway responsible for immunomodulatory effect of MSC EVs in ARDS.

[1]  D. Brazil,et al.  MSC extracellular vesicles modulate human macrophages in ARDS towards anti-inflammatory phenotype via transfer of miRNA181-a and PTEN-pSTAT5-SOCS1 signalling , 2021, Mechanisms of lung injury and repair.

[2]  C. D. dos Santos,et al.  Research Progress on Strategies that can Enhance the Therapeutic Benefits of Mesenchymal Stromal Cells in Respiratory Diseases With a Specific Focus on Acute Respiratory Distress Syndrome and Other Inflammatory Lung Diseases , 2021, Frontiers in Pharmacology.

[3]  J. Nolan,et al.  Generation and Application of a Reporter Cell Line for the Quantitative Screen of Extracellular Vesicle Release , 2021, Frontiers in Pharmacology.

[4]  M. Matthay,et al.  Healthy versus inflamed lung environments differentially affect mesenchymal stromal cells , 2021, European Respiratory Journal.

[5]  K. Delucchi,et al.  Mesenchymal stromal cell extracellular vesicles rescue mitochondrial dysfunction and improve barrier integrity in clinically relevant models of ARDS , 2020, European Respiratory Journal.

[6]  M. Curley,et al.  Phenotypes and personalized medicine in the acute respiratory distress syndrome , 2020, Intensive Care Medicine.

[7]  D. McAuley,et al.  Mesenchymal stromal cells for acute respiratory distress syndrome (ARDS), sepsis, and COVID-19 infection: optimizing the therapeutic potential , 2020, Expert review of respiratory medicine.

[8]  X. Biao,et al.  Corrigendum to "miRNA-181a over-expression in mesenchymal stem cell-derived exosomes influenced inflammatory response after myocardial ischemia-reperfusion injury" [Life Sci. 232 (2019) 116632]. , 2020, Life sciences.

[9]  A. Gordon,et al.  Subphenotypes in critical care: translation into clinical practice. , 2020, The Lancet. Respiratory medicine.

[10]  D. Brazil,et al.  pSTAT5-SOCS1 signalling as a novel pathway in macrophage metabolic reprogramming by Mesenchymal Stromal Cells (MSCs) in ARDS , 2020 .

[11]  M. Matthay,et al.  Extracellular Vesicles: A New Frontier for Research in Acute Respiratory Distress Syndrome. , 2020, American journal of respiratory cell and molecular biology.

[12]  K. Delucchi,et al.  Development and validation of parsimonious algorithms to classify acute respiratory distress syndrome phenotypes: a secondary analysis of randomised controlled trials. , 2020, The Lancet. Respiratory medicine.

[13]  Ai-ran Liu,et al.  Therapeutic potential of mesenchymal stem/stromal cell-derived secretome and vesicles for lung injury and disease , 2019, Expert opinion on biological therapy.

[14]  A. Abraham,et al.  Mesenchymal stem cell‐derived extracellular vesicles for the treatment of acute respiratory distress syndrome , 2019, Stem cells translational medicine.

[15]  M. Wurfel,et al.  Alveolar Macrophage Transcriptional Programs are Associated with Outcomes in Acute Respiratory Distress Syndrome. , 2019, American journal of respiratory and critical care medicine.

[16]  A. Randolph,et al.  The acute respiratory distress syndrome. , 1996, New England Journal of Medicine.

[17]  D. McAuley,et al.  Hypercapnic acidosis induces mitochondrial dysfunction and impairs the ability of mesenchymal stem cells to promote distal lung epithelial repair , 2019, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  Jing Xu,et al.  Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines , 2018, Journal of Extracellular Vesicles.

[19]  Kevin L. Delucchi,et al.  Latent class analysis of ARDS subphenotypes: a secondary analysis of the statins for acutely injured lungs from sepsis (SAILS) study , 2018, Intensive Care Medicine.

[20]  J. Laffey,et al.  Acute respiratory distress syndrome subphenotypes and differential response to simvastatin: secondary analysis of a randomised controlled trial. , 2018, The Lancet. Respiratory medicine.

[21]  J. Laffey,et al.  Negative trials in critical care: why most research is probably wrong. , 2018, The Lancet. Respiratory medicine.

[22]  L. Liao,et al.  Efficacy of intracellular immune checkpoint-silenced DC vaccine , 2018, JCI insight.

[23]  Jisung Park,et al.  Pharmacologic inhibition of STAT5 in acute myeloid leukemia , 2018, Leukemia.

[24]  S. Singh,et al.  SOCS Proteins as Regulators of Inflammatory Responses Induced by Bacterial Infections: A Review , 2017, Front. Microbiol..

[25]  E. K. Cunningham,et al.  Mesenchymal Stromal Cells Modulate Macrophages in Clinically Relevant Lung Injury Models by Extracellular Vesicle Mitochondrial Transfer , 2017, American journal of respiratory and critical care medicine.

[26]  Wonyong Lee,et al.  PTEN drives Th17 cell differentiation by preventing IL-2 production , 2017, The Journal of experimental medicine.

[27]  H. Wong,et al.  SOCS1 is a negative regulator of metabolic reprogramming during sepsis. , 2017, JCI insight.

[28]  K. Famous,et al.  Acute Respiratory Distress Syndrome Subphenotypes Respond Differently to Randomized Fluid Management Strategy , 2016, American journal of respiratory and critical care medicine.

[29]  P. Macpherson,et al.  Suppressor of cytokine signaling (SOCS) proteins are induced by IL-7 and target surface CD127 protein for degradation in human CD8 T cells. , 2016, Cellular immunology.

[30]  J. Johnston,et al.  Reduced epithelial suppressor of cytokine signalling 1 in severe eosinophilic asthma , 2016, European Respiratory Journal.

[31]  M. Matthay,et al.  Mitochondrial Transfer via Tunneling Nanotubes is an Important Mechanism by Which Mesenchymal Stem Cells Enhance Macrophage Phagocytosis in the In Vitro and In Vivo Models of ARDS , 2016, Stem cells.

[32]  Min Zhou,et al.  Cigarette smoke-induced lung inflammation in COPD mediated via LTB4/BLT1/SOCS1 pathway , 2015, International journal of chronic obstructive pulmonary disease.

[33]  Ann Lohner.  "Long-Term Exposure" , 2016 .

[34]  Simon C Watkins,et al.  Mesenchymal stem cells use extracellular vesicles to outsource mitophagy and shuttle microRNAs , 2015, Nature Communications.

[35]  Qi Hao,et al.  Therapeutic Effects of Human Mesenchymal Stem Cell-derived Microvesicles in Severe Pneumonia in Mice. , 2015, American journal of respiratory and critical care medicine.

[36]  G. Perkins,et al.  Simvastatin in the acute respiratory distress syndrome. , 2014, The New England journal of medicine.

[37]  Amjad Ali,et al.  Formal Modelling of Toll like Receptor 4 and JAK/STAT Signalling Pathways: Insight into the Roles of SOCS-1, Interferon-β and Proinflammatory Cytokines in Sepsis , 2014, PloS one.

[38]  L. King,et al.  Diverse macrophage populations mediate acute lung inflammation and resolution. , 2014, American journal of physiology. Lung cellular and molecular physiology.

[39]  Adam Williams,et al.  The microRNA miR-181 is a critical cellular metabolic rheostat essential for NKT cell ontogenesis and lymphocyte development and homeostasis. , 2013, Immunity.

[40]  M. Matthay,et al.  Therapeutic effects of human mesenchymal stem cells in ex vivo human lungs injured with live bacteria. , 2013, American journal of respiratory and critical care medicine.

[41]  M. Matthay,et al.  Human mesenchymal stem cells reduce mortality and bacteremia in gram-negative sepsis in mice in part by enhancing the phagocytic activity of blood monocytes. , 2012, American journal of physiology. Lung cellular and molecular physiology.

[42]  R. Barker,et al.  Suppressor of cytokine signaling (SOCS)1 is a key determinant of differential macrophage activation and function , 2011, Journal of leukocyte biology.

[43]  D. McAuley,et al.  A randomized clinical trial of hydroxymethylglutaryl- coenzyme a reductase inhibition for acute lung injury (The HARP Study). , 2011, American journal of respiratory and critical care medicine.

[44]  T. Ikezoe,et al.  Long-term exposure of leukemia cells to multi-targeted tyrosine kinase inhibitor induces activations of AKT, ERK and STAT5 signaling via epigenetic silencing of the PTEN gene , 2010, Leukemia.

[45]  Avrum Spira,et al.  MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium , 2009, Proceedings of the National Academy of Sciences.

[46]  P. Hart,et al.  SOCS1 Regulates the IFN but Not NFκB Pathway in TLR-Stimulated Human Monocytes and Macrophages1 , 2008, The Journal of Immunology.

[47]  E. Benveniste,et al.  Expression and Functional Significance of SOCS-1 and SOCS-3 in Astrocytes1 , 2008, The Journal of Immunology.

[48]  K. Heeg,et al.  Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins. , 2008, Immunobiology.

[49]  J. Baker,et al.  Expression and Functional Significance of SOCS-1 and SOCS-3 in Astrocytes , 2008 .

[50]  Masato Kubo,et al.  SOCS proteins, cytokine signalling and immune regulation , 2007, Nature Reviews Immunology.

[51]  G. Bernard,et al.  Acute lung injury and the acute respiratory distress syndrome: a clinical review , 2007, The Lancet.

[52]  Paul J Hertzog,et al.  Suppressor of cytokine signaling 1 negatively regulates Toll-like receptor signaling by mediating Mal degradation , 2006, Nature Immunology.

[53]  W. Heath,et al.  SOCS1: a potent and multifaceted regulator of cytokines and cell-mediated inflammation. , 2006, Tissue antigens.

[54]  D. Prockop,et al.  Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. , 2006, Cytotherapy.

[55]  W. Alexander,et al.  The role of suppressors of cytokine signaling (SOCS) proteins in regulation of the immune response. , 2004, Annual review of immunology.

[56]  Warren S. Alexander,et al.  Suppressors of cytokine signalling (SOCS) in the immune system , 2002, Nature Reviews Immunology.

[57]  M. Fujimoto,et al.  IFN Regulatory Factor-1-Mediated Transcriptional Activation of Mouse STAT-Induced STAT Inhibitor-1 Gene Promoter by IFN-γ1 , 2000, The Journal of Immunology.

[58]  S. Akira,et al.  Structure and function of a new STAT-induced STAT inhibitor , 1997, Nature.