Inhibition of CX3CL1 (Fractalkine) Improves Experimental Autoimmune Myositis in SJL/J Mice

Abstract

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-α, IFN-γ, 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.

Fractalkine and its receptor, CX3CR1, promote hypertensive interstitial fibrosis in the kidney

“…In support of this finding, it has been reported that fractalkine/CX3CL1 is expressed on infiltrating mononuclear cells, such as endothelial cells. 23 Second, the interaction of endothelial cells and macrophages may be important. Role of fractalkine-CX3CR1 in hypertensive kidney injury K Shimizu et al Activated macrophages expressing CX3CR1 might produce proinflammatory cytokines and chemokines, which activate endothelial cells and subsequently promote the inflammatory process.…”

Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivo

“…Inflammatory cell infiltration and necrotic muscle fiber are evident in this model. In the muscle of animals with experimental autoimmune myositis, CD4ϩ T cells are mainly located in the perimysium and CD8ϩ T cells are chiefly located in the endomysium and surrounded nonnecrotic muscle fibers (12). We also showed that expression of TNF␣, IFN␥, and perforin was up-regulated in the muscles of mice with experimental autoimmune myositis (12).…”

“…In the muscle of animals with experimental autoimmune myositis, CD4ϩ T cells are mainly located in the perimysium and CD8ϩ T cells are chiefly located in the endomysium and surrounded nonnecrotic muscle fibers (12). We also showed that expression of TNF␣, IFN␥, and perforin was up-regulated in the muscles of mice with experimental autoimmune myositis (12). Moreover, expression of intercellular adhesion molecule 1 was increased in the muscles (13).…”

“…The experimental protocol was approved by the Institutional Animal Care and Use Committee of Tokyo Medical and Dental University. The method for induction of experimental autoimmune myositis has been described previously (12). Briefly, 5-week-old male SJL/J mice were purchased from Charles River Japan (Yokohama, Japan).…”

“…We have developed an experimental model of autoimmune myositis in mice, which is induced by repeated immunization with rabbit myosin (12). Inflammatory cell infiltration and necrotic muscle fiber are evident in this model.…”