Suzuki Fumihito, Nanki Toshihiro, Imai Toshio, Kikuchi Hirotoshi, Hirohata Shunsei, Kohsaka Hitoshi, Miyasaka Nobuyuki
Department of Medicine and Rheumatology, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
J Immunol. 2005 Nov 15;175(10):6987-96. doi: 10.4049/jimmunol.175.10.6987.
Idiopathic inflammatory myopathy is a chronic inflammatory muscle disease characterized by mononuclear cell infiltration in the skeletal muscle. The infiltrated inflammatory cells express various cytokines and cytotoxic molecules. Chemokines are thought to contribute to the inflammatory cell migration into the muscle. We induced experimental autoimmune myositis (EAM) in SJL/J mice by immunization with rabbit myosin and CFA. In the affected muscles of EAM mice, CX3CL1 (fractalkine) was expressed on the infiltrated mononuclear cells and endothelial cells, and its corresponding receptor, CX3CR1, was expressed on the infiltrated CD4 and CD8 T cells and macrophages. Treatment of EAM mice with anti-CX3CL1 mAb significantly reduced the histopathological myositis score, the number of necrotic muscle fibers, and infiltration of CD4 and CD8 T cells and macrophages. Furthermore, treatment with anti-CX3CL1 mAb down-regulated the mRNA expression of TNF-alpha, IFN-gamma, and perforin in the muscles. Our results suggest that CX3CL1-CX3CR1 interaction plays an important role in inflammatory cell migration into the muscle tissue of EAM mice. The results also point to the potential therapeutic usefulness of CX3CL1 inhibition and/or blockade of CX3CL1-CX3CR1 interaction in idiopathic inflammatory myopathy.
特发性炎性肌病是一种慢性炎性肌肉疾病,其特征为骨骼肌中有单核细胞浸润。浸润的炎性细胞表达多种细胞因子和细胞毒性分子。趋化因子被认为有助于炎性细胞迁移至肌肉。我们通过用兔肌球蛋白和弗氏完全佐剂免疫SJL/J小鼠诱导了实验性自身免疫性肌炎(EAM)。在EAM小鼠的受累肌肉中,CX3CL1(fractalkine)在浸润的单核细胞和内皮细胞上表达,其相应受体CX3CR1在浸润的CD4和CD8 T细胞及巨噬细胞上表达。用抗CX3CL1单克隆抗体治疗EAM小鼠可显著降低组织病理学肌炎评分、坏死肌纤维数量以及CD4和CD8 T细胞及巨噬细胞的浸润。此外,用抗CX3CL1单克隆抗体治疗可下调肌肉中TNF-α、IFN-γ和穿孔素的mRNA表达。我们的结果表明,CX3CL1 - CX3CR1相互作用在炎性细胞迁移至EAM小鼠肌肉组织中起重要作用。这些结果还表明CX3CL1抑制和/或阻断CX3CL1 - CX3CR1相互作用在特发性炎性肌病中具有潜在的治疗价值。