Abstract
Arthritis is one of the most common complications of human brucellosis, but its pathogenic mechanisms have not been elucidated. Fibroblast-like synoviocytes (FLS) are known to be central mediators of joint damage in inflammatory arthritides through the production of matrix metalloproteinases (MMPs) that degrade collagen and of cytokines and chemokines that mediate the recruitment and activation of leukocytes. In this study we show that Brucella abortus infects and replicates in human FLS (SW982 cell line) in vitro and that infection results in the production of MMP-2 and proinflammatory mediators (interleukin-6 [IL-6], IL-8, monocyte chemotactic protein 1 [MCP-1], and granulocyte-macrophage colony-stimulating factor [GM-CSF]). Culture supernatants from Brucella-infected FLS induced the migration of monocytes and neutrophils in vitro and also induced these cells to secrete MMP-9 in a GM-CSF- and IL-6-dependent fashion, respectively. Reciprocally, culture supernatants from Brucella-infected monocytes and neutrophils induced FLS to produce MMP-2 in a tumor necrosis factor alpha (TNF-α)-dependent fashion. The secretion of proinflammatory mediators and MMP-2 by FLS did not depend on bacterial viability, since it was also induced by heat-killed B. abortus (HKBA) and by a model Brucella lipoprotein (L-Omp19). These responses were mediated by the recognition of B. abortus antigens through Toll-like receptor 2. The intra-articular injection of HKBA or L-Omp19 into the knee joint of mice resulted in the local induction of the proinflammatory mediators MMP-2 and MMP-9 and in the generation of a mixed inflammatory infiltrate. These results suggest that FLS, and phagocytes recruited by them to the infection focus, may be involved in joint damage during brucellar arthritis through the production of MMPs and proinflammatory mediators.
Highlights
Arthritis is one of the most common complications or focalizations of human brucellosis and may be caused by different Brucella species
In this study we show that Brucella abortus infects and replicates in human Fibroblast-like synoviocytes (FLS) (SW982 cell line) in vitro and that infection results in the production of matrix metalloproteinases (MMPs)-2 and proinflammatory mediators
This was confirmed by enzyme-linked immunosorbent assay (ELISA), which revealed significantly increased levels of MMP-2 in supernatants of infected cells compared to uninfected cells (Fig. 1C). By both methods the magnitude of MMP-2 release was related directly to the MOI used. These results indicate that B. abortus can infect and replicate in human FLS in which it induces the secretion of MMP-2
Summary
Arthritis is one of the most common complications or focalizations of human brucellosis and may be caused by different Brucella species. Image studies have revealed cartilage loss and bone erosion in brucellar arthritis affecting different joints [3, 28]. These lesions may eventually lead to permanent joint dysfunction. Septic arthritis may be caused by different bacteria, among which Staphylococcus aureus is the leading cause and has been commonly used in animal models to study the pathogenesis of this condition [4]. MMPs comprise a family of calcium- and zinc-dependent proteinases that degrade collagens and other extracellular matrix proteins through selective and overlapping substrate specificities [5, 36] These enzymes have many physiological functions but may have detrimental effects when their levels are highly increased, as occurs in many inflammatory processes. In a recent study we found a high level of gelatinase activity in the synovial fluid of a patient with prepatellar bursitis due to Brucella abortus, as revealed by zymography, and confirmed the presence of high levels of MMP-9 by an enzyme-linked immunosorbent assay (ELISA), which suggests that MMPs may be involved in the osteoarticular damage associated with Brucella infection [52]
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