Norepinephrine signaling, believed to contribute to Raynaud’s phenomenon, also may be driving fibrosis development in patients with scleroderma, according to a study that opens up for new research into the molecular mechanisms of skin fibrosis.
The study, “Mechanistic insight into the norepinephrine-induced fibrosis in systemic sclerosis,” published in the journal Scientific Reports, suggested that avoiding cold and stress could be crucial for slowing fibrosis progression.
Norepinephrine (aka noradrenaline in Europe) is a neurotransmitter crucial for regulating blood pressure in response to stress, by constricting blood vessels. Since patients with Raynaud’s improve when treated with drugs blocking norepinephrine, researchers believe it is involved in the development of Raynaud’s symptoms.
Earlier studies have shown that norepinephrine affects the properties of skin fibroblasts — a cell type involved in the development of fibrosis. But, so far, few studies have investigated if the neurotransmitter is involved in fibrotic processes.
Researchers at Gunma University Graduate School of Medicine in Japan isolated skin fibroblasts from six patients with scleroderma and six controlled subjects, and grew them in the lab. When treating the cells with norepinephrine, those isolated from patients released more of an immune factor called interleukin (IL)-6.
IL-6 is increased in the skin of patients in early stages of diffuse cutaneous scleroderma. Earlier studies also reported that when looking at skin cells in a lab dish, IL-6, when bound to its soluble receptor in cells, triggers a fibrotic behavior on them. When IL-6 binds to its receptor present outside the cells, the complex docks into another structure on the cell surface to initiate cellular changes.
Molecular analysis showed that this was an effect mediated by one of epinephrine’s two receptors, called AR-beta. Activating the other receptor, known as AR-alpha, had the opposite effect.
Researchers also noted that when treating the cells with norepinephrine and another molecule known to trigger fibrosis, called ET-1, the cells produced even more IL-6.
Cells stimulated with norepinephrine also produced more collagen type 1, but only when researchers added the soluble receptor into the mixture.
Researchers believe the findings may explain why skin fibrosis often starts in the fingertips and toes (regions also affected by Raynaud’s) in patients with scleroderma.
“We for the first time elucidated the possible link between peripheral circulation disturbance and tissue fibrosis via NE [norepinephrine] stimulation, which will provide us with novel therapeutic strategy for SSc [scleroderma],” the research team wrote in its report. “The avoidance of cold exposure or emotional stress may attribute to the suppression of fibrosis, as well as Raynaud’s phenomenon in SSc.”