Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases
Potential Role of Fibroblast-Like Synoviocytes in Joint Damage Induced by Brucella abortus Infection through Production and Induction of Matrix Metalloproteinases
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DOI：
10.1128/iai.05408-11
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发表时间：
2011-09-01
影响因子：
3.1
通讯作者：
Victoria Delpino, M.
中科院分区：
文献类型：
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作者：
Scian, Romina;Barrionuevo, Paula;Victoria Delpino, M.
关节炎是人类布鲁氏菌病最常见的并发症之一，但其致病机制尚未阐明。已知成纤维细胞样滑膜细胞（FLS）通过产生降解胶原蛋白的基质金属蛋白酶（MMP）以及介导白细胞募集和激活的细胞因子和趋化因子，是炎症性关节炎关节损伤的中心介质。在这项研究中，我们证明流产布鲁氏菌在体外感染人 FLS（SW982 细胞系）并在其中复制，感染导致 MMP-2 和促炎介质（白细胞介素 6 [IL-6]、IL-8、单核细胞趋化蛋白 1 [MCP-1] 和粒细胞巨噬细胞集落刺激因子 [GM-CSF]）的产生。来自布鲁氏菌感染的 FLS 的培养上清液在体外诱导单核细胞和中性粒细胞的迁移，并且还诱导这些细胞分别以 GM-CSF 和 IL-6 依赖性方式分泌 MMP-9。相反，来自布鲁氏菌感染的单核细胞和中性粒细胞的培养上清液诱导 FLS 以肿瘤坏死因子 α (TNF-α) 依赖性方式产生 MMP-2。 FLS 分泌促炎介质和 MMP-2 并不依赖于细菌活力，因为它也是由热灭活的流产布鲁氏菌 (HKBA) 和模型布鲁氏菌脂蛋白 (L-Omp19) 诱导的。这些反应是通过 Toll 样受体 2 识别流产布鲁氏菌抗原来介导的。将 HKBA 或 L-Omp19 关节内注射到小鼠膝关节中，导致局部诱导促炎介质 MMP-2 和 MMP-9，并产生混合炎症浸润。这些结果表明，FLS 以及它们招募到感染灶的吞噬细胞可能通过产生 MMP 和促炎介质参与布氏关节炎期间的关节损伤。
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-alpha)-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.