1. Brucella abortus Promotes a Fibrotic Phenotype in Hepatic Stellate Cells, with Concomitant Activation of the Autophagy Pathway.
- Author
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Arriola Benitez PC, Pesce Viglietti AI, Herrmann CK, Dennis VA, Comerci DJ, Giambartolomei GH, and Delpino MV
- Subjects
- Apoptosis physiology, Beclin-1 metabolism, Brucellosis metabolism, Brucellosis microbiology, Brucellosis pathology, Caspase 3 metabolism, Cell Line, Collagen metabolism, Fibrosis metabolism, Hepatic Stellate Cells metabolism, Humans, Liver metabolism, Liver microbiology, Liver pathology, Liver Cirrhosis metabolism, Liver Cirrhosis microbiology, Liver Cirrhosis pathology, Matrix Metalloproteinase 9 metabolism, Phenotype, Signal Transduction physiology, Transforming Growth Factor beta1 metabolism, Type IV Secretion Systems metabolism, Up-Regulation physiology, Autophagy physiology, Brucella abortus pathogenicity, Fibrosis microbiology, Fibrosis pathology, Hepatic Stellate Cells microbiology, Hepatic Stellate Cells pathology
- Abstract
The liver is frequently affected in patients with active brucellosis. The present study demonstrates that Brucella abortus infection induces the activation of the autophagic pathway in hepatic stellate cells to create a microenvironment that promotes a profibrogenic phenotype through the induction of transforming growth factor-β1 (TGF-β1), collagen deposition, and inhibition of matrix metalloproteinase-9 (MMP-9) secretion. Autophagy was revealed by upregulation of the LC3II/LC3I ratio and Beclin-1 expression as well as inhibition of p62 expression in infected cells. The above-described findings were dependent on the type IV secretion system (VirB) and the secreted BPE005 protein, which were partially corroborated using the pharmacological inhibitors wortmannin, a phosphatidyl inositol 3-kinase inhibitor, and leupeptin plus E64 (inhibitors of lysosomal proteases). Activation of the autophagic pathway in hepatic stellate cells during Brucella infection could have an important contribution to attenuating inflammatory hepatic injury by inducing fibrosis. However, with time, B. abortus infection induced Beclin-1 cleavage with concomitant cleavage of caspase-3, indicating the onset of apoptosis of LX-2 cells, as was confirmed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay and Hoechst staining. These results demonstrate that the cross talk of LX-2 cells and B. abortus induces autophagy and fibrosis with concomitant apoptosis of LX-2 cells, which may explain some potential mechanisms of liver damage observed in human brucellosis., (Copyright © 2017 American Society for Microbiology.)
- Published
- 2017
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