Rulli Nestor E, Guglielmotti Angelo, Mangano Giorgina, Rolph Michael S, Apicella Claudia, Zaid Ali, Suhrbier Andreas, Mahalingam Suresh
Faculty of Applied Science, University of Canberra, Canberra, ACT, Australia.
Arthritis Rheum. 2009 Aug;60(8):2513-23. doi: 10.1002/art.24682.
Alphaviruses such as chikungunya virus, Sindbis virus, o'nyong-nyong virus, Mayaro virus, and Ross River virus (RRV), are commonly associated with arthralgias and overt arthritides worldwide. Understanding the processes by which arthritogenic viruses cause disease is a prerequisite in the quest for better treatments. In this regard, we have recently established that monocyte/macrophages are mediators of alphavirus-induced arthritis in mice. We hypothesized that chemokines associated with monocyte/macrophage recruitment may play an important role in disease. The aim of the present investigations was to determine whether bindarit, an inhibitor of monocyte chemotactic protein (MCP) synthesis, could ameliorate alphavirus-induced rheumatic disease in mice.
Using our recently developed mouse model of RRV-induced arthritis, which has many characteristics of RRV disease (RRVD) in humans, the effects of bindarit treatment on RRVD in mice were determined via histologic analyses, immunohistochemistry, flow cytometry, real-time polymerase chain reaction analysis, enzyme-linked immunosorbent assay, and electrophoretic mobility shift assay.
Bindarit-treated RRV-infected mice developed mild disease and had substantially reduced tissue destruction and inflammatory cell recruitment as compared with untreated RRV-infected mice. The virus load in the tissues was not affected by bindarit treatment. Bindarit exhibited its activity by down-regulating MCPs, which in turn led to inhibition of cell infiltration and lower production of NF-kappaB and tumor necrosis factor alpha, which are involved in mediating tissue damage.
Our data support the use of inhibitors of MCP production in the treatment of arthritogenic alphavirus syndromes and suggest that bindarit may be useful in treating RRVD and other alphavirus-induced arthritides in humans.
诸如基孔肯雅病毒、辛德毕斯病毒、奥尼永尼永病毒、马亚罗病毒和罗斯河病毒（RRV）等甲病毒在全球范围内通常与关节痛和明显的关节炎相关。了解致关节炎病毒引发疾病的过程是寻求更好治疗方法的先决条件。在这方面，我们最近证实单核细胞/巨噬细胞是甲病毒诱导的小鼠关节炎的介质。我们推测与单核细胞/巨噬细胞募集相关的趋化因子可能在疾病中起重要作用。本研究的目的是确定单核细胞趋化蛋白（MCP）合成抑制剂宾达里是否能改善甲病毒诱导的小鼠风湿性疾病。
利用我们最近开发的RRV诱导的关节炎小鼠模型，该模型具有人类RRV疾病（RRVD）的许多特征，通过组织学分析、免疫组织化学、流式细胞术、实时聚合酶链反应分析、酶联免疫吸附测定和电泳迁移率变动分析来确定宾达里治疗对小鼠RRVD的影响。
与未治疗的RRV感染小鼠相比，接受宾达里治疗的RRV感染小鼠病情较轻，组织破坏和炎症细胞募集明显减少。宾达里治疗对组织中的病毒载量没有影响。宾达里通过下调MCP发挥其活性，进而导致细胞浸润受到抑制，以及参与介导组织损伤的核因子κB和肿瘤坏死因子α的产生减少。
我们的数据支持使用MCP产生抑制剂治疗致关节炎甲病毒综合征，并表明宾达里可能对治疗人类RRVD和其他甲病毒诱导的关节炎有用。
