Sultana Sahin, Adhikary Rana, Bishayi Biswadev
Department of Physiology, Immunology Laboratory, University of Calcutta, University Colleges of Science and Technology, 92 APC Road, Calcutta, West Bengal, 700009, India.
Inflammation. 2017 Jun;40(3):1028-1050. doi: 10.1007/s10753-017-0547-z.
Despite advancement in the field of antibiotics septic arthritis remains a serious concern till date. Staphylococcus aureus is the most common bacterium that causes septic arthritis. Severity of this disease is directly correlated with chronic inflammation induced by proinflammatory cytokines like TNF-α, interleukin (IL)-1β, IL-6, and induction of matrix metalloproteinases (MMPs) including MMP-2. The objective of our study was to evaluate the role of MMP-2 and tumor necrosis factor receptor 1 (TNFR1) in the pathogenesis of S. aureus infection-induced septic arthritis. Mice were infected with live S. aureus (5 × 10 cells/ml) followed by administration of MMP-2 inhibitor and TNFR1 antibody. Arthritis index showed highest reduction in severity of arthritis in mice treated with both MMP-2 inhibitor and TNFR1 antibody after infection. Combined neutralization of MMP-2 and TNFR1 led to marked diminution in bacterial count in the combined group. Lowest levels of pro inflammatory cytokines like TNF-α, IL-1β, IL-6, and IFN-γ were observed in both serum and synovial tissues indicating maximum protection in S. aureus arthritis during combination treatment. Increment in the level of IL-10 in the combination group could be positively correlated with the recovery of arthritis. Similarly, expressions of COX-2 and iNOS, markers of acute inflammation were also significantly reduced in the combination group due to resolution of inflammation. Levels of O2 and NO also showed a significant fall in case of the group treated with MMP-2 inhibitor and TNFR1 antibody both. Neutralization of both MMP-2 and TNFR1 caused rapid decline in recruitment of neutrophil and macrophages in the synovial tissues as evident from reduced MPO and MCP-1 levels, respectively, compared to other groups. Overall, it can be suggested that administration of MMP-2 inhibitor and TNFR1 antibody in combination is protective against the severity of inflammation and cartilage destruction associated with S. aureus infection-induced septic arthritis by altering the levels of cytokines.
尽管抗生素领域取得了进展，但迄今为止，化脓性关节炎仍然是一个严重问题。金黄色葡萄球菌是引起化脓性关节炎最常见的细菌。这种疾病的严重程度与促炎细胞因子如肿瘤坏死因子-α（TNF-α）、白细胞介素（IL）-1β、IL-6诱导的慢性炎症以及包括基质金属蛋白酶-2（MMP-2）在内的基质金属蛋白酶（MMPs）的诱导直接相关。我们研究的目的是评估MMP-2和肿瘤坏死因子受体1（TNFR1）在金黄色葡萄球菌感染诱导的化脓性关节炎发病机制中的作用。小鼠感染活的金黄色葡萄球菌（5×10个细胞/毫升），随后给予MMP-2抑制剂和TNFR1抗体。关节炎指数显示，感染后用MMP-2抑制剂和TNFR1抗体治疗的小鼠关节炎严重程度降低最为显著。MMP-2和TNFR1的联合中和导致联合组细菌数量显著减少。在血清和滑膜组织中均观察到TNF-α、IL-1β、IL-6和干扰素-γ等促炎细胞因子水平最低，表明联合治疗期间对金黄色葡萄球菌性关节炎有最大程度的保护作用。联合组中IL-10水平的升高与关节炎的恢复呈正相关。同样，由于炎症消退，联合组中急性炎症标志物COX-2和诱导型一氧化氮合酶（iNOS）的表达也显著降低。在用MMP-2抑制剂和TNFR1抗体治疗的组中，O2和NO水平也显著下降。与其他组相比，MMP-2和TNFR1的中和导致滑膜组织中中性粒细胞和巨噬细胞募集迅速减少，分别从MPO和MCP-1水平降低明显看出。总体而言，可以认为联合给予MMP-2抑制剂和TNFR1抗体可通过改变细胞因子水平，对与金黄色葡萄球菌感染诱导的化脓性关节炎相关的炎症严重程度和软骨破坏起到保护作用。
