Abstract
Understanding rheumatic diseases from the perspective of chemokine biology has shaped and will continue to shape our approach for targeted drug design. Among different kinds of chemokines, fractalkine/CX3CL1 has been found to play an important role in inflammation, portraying unique functional, and structural characteristics. This review summarizes the emerging role of fractalkine/CX3CL1 from a functional and clinical perspective and provides evidence to validate it as a potential therapeutic target in rheumatic diseases such as rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, scleroderma, as well as diseases related to vascular inflammation. From this, recent studies investigating potential therapeutic agents against fractalkine/CX3CL1’s role in pathology have shown promise.
Highlights
s syndrome (SS) Systemic lupus erythematosus (SLE) Scleroderma Systemic inflammationExpression in macrophages, fibroblasts, endothelial, and dendritic cells in rheumatoid arthritis (RA) synovial tissue (ST) Elevated levels of soluble fractalkine/CX3CL1 in RA synovial fluid (SF) Fractalkine/CX3CL1 levels were significantly elevated in RA SF compared to the SF from osteoarthritis patients Fractalkine/CX3CL1 mRNA expression significantly increased by TNF-a stimulation IFN-γ and tumor necrosis factorα (TNF-α) synergistically induce fractalkine/CX3CL1 expression Threefold increase in CX3CR1 surface expression on CD8+ T cells compared to healthy subjects RA SF depleted of fractalkine/CX3CL1 exhibits a lower angiogenic effect as compared to control SF Fractalkine/CX3CL1 is significantly expressed in rheumatoid vasculitis patients where expression levels correlate to severity of vasculitis Serum levels are ∼1.8-fold higher than RA patient and ∼3.6-fold higher than healthy patients Soluble serum fractalkine/CX3CL1 levels are higher in patients with SLE than RA and SS Serum expression of fractal kine/CX3CL1 was significantly higher in SLE patients compared to healthy controls Li et al (2010a) proposed CX3CR1 as an indicator in clinical surveillance of SLE based on mRNA analysis Enhanced fractalkine/CX3CL1 expression in affected skin and lung tissues of patients with cutaneous scleroderma 429I and 480M polymorphisms are significantly increased in scleroderma patients with pulmonary arterial hypertension Increased susceptibility to scleroderma is associated with the 249II CX3CRI polymorphism Fractalkine/CX3CL1 induces a cardiodepressive effect on peripheral blood mononuclear cells (PBMCs) in inflammatory cardiomyopathy (CMi) patients Through in vivo and in vitro models, fractalkine/CX3CL1 induces angiogenesis in HepG2 cells
INFLAMMATION AND CHEMOKINES Chemokines are small molecular weight heparin-binding proteins that play important roles in the recruitment and retention of inflammatory cells at the site of inflammation or injury by their chemotactic activity
This review summarizes the emerging role of fractalkine/CX3CL1 from a functional and clinical perspective and provides evidence to validate it as a potential therapeutic target in rheumatic diseases such as rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, scleroderma, as well as diseases related to vascular inflammation
Summary
Expression in macrophages, fibroblasts, endothelial, and dendritic cells in RA ST Elevated levels of soluble fractalkine/CX3CL1 in RA SF Fractalkine/CX3CL1 levels were significantly elevated in RA SF compared to the SF from osteoarthritis patients Fractalkine/CX3CL1 mRNA expression significantly increased by TNF-a stimulation IFN-γ and TNF-α synergistically induce fractalkine/CX3CL1 expression Threefold increase in CX3CR1 surface expression on CD8+ T cells compared to healthy subjects RA SF depleted of fractalkine/CX3CL1 exhibits a lower angiogenic effect as compared to control SF Fractalkine/CX3CL1 is significantly expressed in rheumatoid vasculitis patients where expression levels correlate to severity of vasculitis Serum levels are ∼1.8-fold higher than RA patient and ∼3.6-fold higher than healthy patients Soluble serum fractalkine/CX3CL1 levels are higher in patients with SLE than RA and SS Serum expression of fractal kine/CX3CL1 was significantly higher in SLE patients compared to healthy controls Li et al (2010a) proposed CX3CR1 as an indicator in clinical surveillance of SLE based on mRNA analysis Enhanced fractalkine/CX3CL1 expression in affected skin and lung tissues of patients with cutaneous scleroderma 429I and 480M polymorphisms are significantly increased in scleroderma patients with pulmonary arterial hypertension Increased susceptibility to scleroderma is associated with the 249II CX3CRI polymorphism Fractalkine/CX3CL1 induces a cardiodepressive effect on PBMCs in inflammatory cardiomyopathy (CMi) patients Through in vivo and in vitro models, fractalkine/CX3CL1 induces angiogenesis in HepG2 cells
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