Brucella abortus Infection Elicited Hepatic Stellate Cell-Mediated Fibrosis Through Inflammasome-Dependent IL-1β Production

Abstract

In human brucellosis, the liver is frequently affected. <i>Brucella abortus</i> triggers a profibrotic response on hepatic stellate cells (HSCs) characterized by inhibition of MMP-9 with concomitant collagen deposition and TGF-β1 secretion through type 4 secretion system (T4SS). Taking into account that it has been reported that the inflammasome is necessary to induce a fibrotic phenotype in HSC, we hypothesized that <i>Brucella</i> infection might create a microenvironment that would promote inflammasome activation with concomitant profibrogenic phenotype in HSCs. <i>B. abortus</i> infection induces IL-1β secretion in HSCs in a T4SS-dependent manner. The expression of caspase-1 (Casp-1), absent in melanoma 2 (AIM2), Nod-like receptor (NLR) containing a pyrin domain 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) was increased in <i>B. abortus</i>-infected HSC. When infection experiments were performed in the presence of glyburide, a compound that inhibits NLRP3 inflammasome, or A151, a specific AIM2 inhibitor, the secretion of IL-1β was significantly inhibited with respect to uninfected controls. The role of inflammasome activation in the induction of a fibrogenic phenotype in HSCs was determined by performing <i>B. abortus</i> infection experiments in the presence of the inhibitors Ac-YVAD-cmk and glyburide. Both inhibitors were able to reverse the effect of <i>B. abortus</i> infection on the fibrotic phenotype in HSCs. Finally, the role of inflammasome in fibrosis was corroborated <i>in vivo</i> by the reduction of fibrotic patches in liver from <i>B. abortus</i>-infected ASC, NLRP, AIM2, and cCasp-1/11 knock-out (KO) mice with respect to infected wild-type mice.