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Abstract
In human brucellosis, the liver is frequently affected. Brucella abortus 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 Brucella infection might create a microenvironment that would promote inflammasome activation with concomitant profibrogenic phenotype in HSCs. B. abortus 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 B. abortus-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 B. abortus infection experiments in the presence of the inhibitors Ac-YVAD-cmk and glyburide. Both inhibitors were able to 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 fibrotic patches in liver from B. abortus-infected ASC, NLRP, AIM2, and cCasp-1/11 knock-out (KO) mice with respect to infected wild-type mice.
Highlights
Human brucellosis is a zoonosis that induces a chronic and debilitating disease caused by Brucella species that manifests itself with a broad clinical spectrum [1, 2]
LX-2 cells were infected with B. abortus and its isogenic B. abortus virB10 mutant, and IL-1β secretion induced by B. abortus was dependent on the expression of a functional type 4 secretion system (T4SS), since the levels or IL-1β did not differ significantly between LX-2 cells infected with B. abortus virB10 mutant and uninfected controls (Figure 1A)
Our results indicated that B. abortus infection induces IL-1β secretion in a mechanism that is dependent on the presence of a functional T4SS
Summary
Human brucellosis is a zoonosis that induces a chronic and debilitating disease caused by Brucella species that manifests itself with a broad clinical spectrum [1, 2]. Liver involvement in human brucellosis is usually documented, given the well-characterized tropism of Brucella for the reticuloendothelial system [1, 2]. The incidence of liver involvement in active brucellosis has ranged from 5 to 53% or more [2]. Inflammasome activation has been documented in several liver diseases. It was established that inflammasome components are present in hepatic stellate cells (HSCs) and could regulate their function [3]. The consequences of activation of inflammasome pathway were confirmed in vivo, demonstrating its key role in liver fibrosis [4]
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