Gyongyi Szabo,
Professor & Vice Chair for Research, Department of Medicine,
University of Massachusetts Medical School
Gyongyi Szabo, MD, PhD, FAASDL, FACP, AGAF is the Worcester Foundation for Biomedical Sciences Endowed Chair, Associate Vice Provost for Interprofessional Education, Professor and Vice Chair of Medicine at the University of Massachusetts Medical School. Dr. Szabo is an internationally recognized leader in the field of liver immunology and inflammation. Her translational research and clinical investigations focus on alcoholic hepatitis, non-alcoholic fatty liver disease and viral hepatitis. She is the lead investigator on an NIH-supported multicenter clinical trial on alcoholic hepatitis. Her laboratory studies molecular mechanisms of inflammation and innate immunity to identify therapeutic targets and to explore translation of bench to bedside opportunities in liver diseases. Her recent research focuses on the role of Toll-like receptor and Nod-like receptor signaling pathways in alcoholic and non-alcoholic fatty liver diseases and the importance of micro-RNAs as biomarkers. In recognition of her contributions to medical research she was recently elected to the Hungarian Academy of Sciences. She serves on the Editorial Board of Hepatology, Nature Reviews Gartoenterology & Hepatology and on the Advisory Board of several agencies including the NIH ExRNA Consortium. She is President of the American Association for the Study of Liver Diseases in 2015.
Circulating Extracellular Vesicles are Biomarkers and Mediators of Alcoholic Liver Disease
A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of inflammatory monocytes and macrophages (MØs). We studied whether these key cellular events were mediated by extracellular vesicles (EVs) in the pathogenesis of ALD. EVs transfer biomaterials, including proteins and microRNAs, and have recently emerged as important effectors of intercellular communication. We also hypothesized that circulating EVs from mice with ALD have a characteristic protein cargo that may serve as biomarker of disease. The total number of circulating EVs was increased in mice with ALD compared to pair-fed controls. Mass spectrometric analysis of circulating EVs revealed a distinct signature of proteins involved in inflammatory responses, cellular development, and cellular movement between ALD EVs and control EVs. We also identified uniquely important proteins in ALD EVs that were not present in control EVs. When ALD EVs were injected intravenously into alcohol naive mice, we found evidence of uptake of ALD EVs in recipient livers in hepatocytes and MØs. Hepatocytes isolated from mice after transfer of ALD EVs, but not control EVs, showed increased monocyte chemoattractant protein 1 mRNA and protein expression, suggesting a biological effect of ALD EVs. Compared to control EV recipient mice, ALD EV recipient mice had increased numbers of F4/80hi cluster of differentiation 11b (CD11b) lo KCs and increased percentages of tumor necrosis factor alpha–positive/interleukin 12/23– positive (inflammatory/M1) KCs and infiltrating monocytes (F4/80intCD11bhi), while the percentage of CD2061CD1631 (anti-inflammatory/M2) KCs was decreased. In vitro, ALD EVs increased tumor necrosis factor alpha and interleukin-1b production in MØs and reduced CD163 and CD206 expression. We identified heat shock protein 90 in ALD EVs as the mediator of ALD-EV- induced MØ activation. In conclusion these results indicate a specific protein signature of ALD EVs and demonstrate a functional role of circulating EVs in mediating KC/MØ activation in the liver.
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