Brucella abortus promotes a fibrotic phenotype in hepatic stellate cells with concomitant autophagy pathway activation.

ARRIOLA BENITEZ P. C.; PESCE VIGLIETTI A. I.; HERRMANN C. K.; DENNIS V. A.; COMERCI D.J.; GIAMBARTOLOMEI G. H.; DELPINO M.V

INFECTION AND IMMUNITY

AMER SOC MICROBIOLOGY

Lugar: Washington; Año: 2018

0019-9567

The liver is frequently affected in patients with active brucellosis. Thepresent study demonstrates that Brucella abortus infection induces the activation ofthe autophagic pathway in hepatic stellate cells to create a microenvironment thatpromotes a profibrogenic phenotype through the induction of transforming growthfactor-1 (TGF-1), collagen deposition, and inhibition of matrix metalloproteinase-9(MMP-9) secretion. Autophagy was revealed by upregulation of the LC3II/LC3I ratioand Beclin-1 expression as well as inhibition of p62 expression in infected cells. Theabove-described findings were dependent on the type IV secretion system (VirB) andthe secreted BPE005 protein, which were partially corroborated using the pharmacologicalinhibitors wortmannin, a phosphatidyl inositol 3-kinase inhibitor, and leupeptinplus E64 (inhibitors of lysosomal proteases). Activation of the autophagic pathwayin hepatic stellate cells during Brucella infection could have an importantcontribution to attenuating inflammatory hepatic injury by inducing fibrosis. However,with time, B. abortus infection induced Beclin-1 cleavage with concomitantcleavage of caspase-3, indicating the onset of apoptosis of LX-2 cells, as was confirmedby the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick endlabeling assay and Hoechst staining. These results demonstrate that the cross talk ofLX-2 cells and B. abortus induces autophagy and fibrosis with concomitant apoptosisof LX-2 cells, which may explain some potential mechanisms of liver damage observedin human brucellosis.