Blocking CCR2 Protein May Ease Scleroderma Symptoms, Mouse Study Suggests
The study, “Antifibrogenic effects of C‐C chemokine receptor type 2 antagonist in a bleomycin‐induced scleroderma model,” was published in the journal Experimental Dermatology.
Systemic scleroderma is characterized by overproduction of collagen that can accumulate in the skin and internal organs.
These fibroblasts also produce chemical signals that can recruit immune system cells to a specific location. This is normally done during the body’s response to an injury, but is overactivated in people with scleroderma.
The MCP-1 protein — an immune system recruitment factor — binds to a receptor known as CCR2 in immune cells. A previous study found that MCP-1 is produced at high levels in the skin and blood vessels of scleroderma patients. In addition, studies in mice found that both MCP-1 and CCR2 are produced by infiltrating immune cells, and that a deficiency in CCR2 eased lung fibrosis.
RS-504393 acts by blocking CCR2 and has been associated with reduced kidney fibrosis in mice.
Researchers in Japan used a mouse model of scleroderma to better assess the potential benefits of RS-504393. The mice were injected daily with a type of antibiotic called bleomycin for four weeks to produce alterations that mimicked scleroderma symptoms.
The mice were split into three groups. One group received a higher dose of RS-504393 (8 mg/kg/day), one took a lower dose (4 mg/kg/day), and one received bleomycin only (controls). RS-504393 was injected six hours before bleomycin, three days per week, for four weeks.
Results showed that RS-504393 suppressed dermal fibrosis and eased skin thickness. Skin thickness was reduced by 10% in the low dosage group and by 18% in the high dosage group compared with controls. The researchers also found reduced levels of collagen and of other proteins involved in the immune response.
The study also revealed reduced infiltration of immune mast cells in treated skin sites of mice given RS-504393. Likewise, skin levels of myofibroblasts — differentiated fibroblasts that play a key role in scleroderma processes — were significantly lower in mice taking the higher dose of RS-504393 than in the controls.
In the lungs, treatment with RS-504393 decreased the severity of bleomycin-induced inflammation and fibrosis, and reduced the amount of collagen by 31% in the low dose group and 40% in the high dose group compared to untreated mice.
“We demonstrated that RS‐504393 inhibited dermal sclerosis and lung fibrosis and reduced the numbers of mast cells and myofibroblasts in the dermis,” the researchers wrote. “These data suggest that CCR2 antagonist RS-504393 may be a therapeutic agent for human scleroderma.”
One limitation of the study, the team said, was that the mice were given RS-504393 before bleomycin. Therefore, the study did not assess the potential benefits of the therapy after the onset of scleroderma.
However, as skin tightening is slowly progressive in scleroderma patients, the researchers believe that RS-504393 could be effective if symptoms are detected early.