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

ARRIOLA BENITEZ, PAULA CONSTANZA; PESCE VIGLIETTI, AYELÉN IVANA; GOMES, MARCO TULIO R.; OLIVEIRA, SERGIO COSTA; QUARLERI, JORGE FABIÁN; GIAMBARTOLOMEI, GUILLERMO HERNÁN; DELPINO, MARÍA VICTORIA

Frontiers in Immunology

Frontiers Media SA

Lugar: Lausana; Año: 2020 vol. 10

In human brucellosis, the liver is frequently affected. Brucella abortus triggers a profibroticresponse on hepatic stellate cells (HSCs) characterized by inhibition of MMP-9 withconcomitant collagen deposition and TGF-b1 secretion through type 4 secretion system(T4SS). Taking into account that it has been reported that the inflammasome isnecessary to induce a fibrotic phenotype in HSC, we hypothesized that Brucella infectionmight create a microenvironment that would promote inflammasome activation withconcomitant profibrogenic phenotype in HSCs. B. abortus infection induces IL-1bsecretion 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) wasincreased in B. abortus-infected HSC. When infection experiments were performed inthe presence of glyburide, a compound that inhibits NLRP3 inflammasome, or A151, aspecific AIM2 inhibitor, the secretion of IL-1b was significantly inhibited with respect touninfected controls. The role of inflammasome activation in the induction of a fibrogenicphenotype in HSCs was determined by performing B. abortus infection experiments inthe presence of the inhibitors Ac-YVAD-cmk and glyburide. Both inhibitors were ableto reverse the effect of B. abortus infection on the fibrotic phenotype in HSCs. Finally,the role of inflammasome in fibrosis was corroborated in vivo by the reduction of fibroticpatches in liver from B. abortus-infected ASC, NLRP, AIM2, and cCasp-1/11 knock-out(KO) mice with respect to infected wild-type mice.