Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo
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(2020) 18:140
RESEARCH
Open Access
Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo Nazli Khodayari1* , Regina Oshins1, L. Shannon Holliday2, Virginia Clark3, Qiang Xiao4, George Marek1, Borna Mehrad1 and Mark Brantly1*
Abstract Background: Alpha-1 antitrypsin deficiency (AATD)-mediated liver disease is a toxic “gain-of-function” inflammation in the liver associated with intracellular retention of mutant alpha-1 antitrypsin. The clinical presentation of the disease includes fibrosis, cirrhosis and liver failure. However, the pathogenic mechanism of AATD-mediated liver disease is not well understood. Here, we investigated the role of plasma extracellular vesicles (EVs) in progression of AATD-mediated liver disease. Methods: EVs were isolated from plasma of AATD individuals with liver disease and healthy controls. Their cytokines and miRNA content were examined by multiplex assay and small RNA sequencing. The bioactivity of EVs was assessed by qPCR, western blot analysis and immunofluorescent experiments using human hepatic stellate cells (HSCs) treated with EVs isolated from control or AATD plasma samples. Results: We have found that AATD individuals have a distinct population of EVs with pathological cytokine and miRNA contents. When HSCs were cultured with AATD plasma derived-EVs, the expression of genes related to the development of fibrosis were significantly amplified compared to those treated with healthy control plasma EVs. Conclusion: AATD individuals have a distinct population of EVs with abnormal cytokine and miRNA contents and the capacity to activate HSCs and mediate fibrosis. Better understanding of the components which cause liver inflammation and fibrogenesis, leading to further liver injury, has the potential to lead to the development of new treatments or preventive strategies to prevent AATD-mediated liver disease. Keywords: Alpha-1 antitrypsin, Extracellular vesicles, Cytokine, miRNA, Liver fibrosis
Background Alpha-1 antitrypsin (AAT), is primarily produced in the liver, contributing to the innate immune system as an anti-inflammatory protein by inhibiting destructive neutrophil proteases [1]. Moreover, AAT has been shown to have anti-inflammatory properties independent of its * Correspondence: [email protected]; [email protected] 1 Division of Pulmonary, Critical Care, and Sleep Medicine, University of Florida, Gainesville, USA Full list of author information is available at the end of the article
antiprotease activity through modulating cellular processes like apoptosis and cytokine expression [2, 3]. Alpha-1 antitrypsin deficiency (AATD) is a common inherited cause of liver disease and the most frequent genetic etiology for pediatric liver disease and transplantation [3]. Z mutation - the most common deficiency allele - results in accumulation of misfolded ZAAT in hepatocytes and monocytes and low levels of circulating AAT which, leads to uncontrolled proteolytic activity in different tissues especially
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