Immune players known as dendritic cells play a key role in scleroderma development in the skin and may represent a new target for effective treatments, a mouse study suggests.
The study, “Regulation of skin fibrosis by RALDH1-producing dermal dendritic cells via retinoic acid-mediated regulatory T cell induction: A role in scleroderma,” was published in the Journal of Dermatological Science.
Scleroderma is an autoimmune disease characterized by thickened skin that’s caused by excessive production of collagen. Immune cells play a central role in scleroderma, with two main types in the skin: macrophages — white blood cells that locate and attack invading bacteria or viruses — and dendritic cells (DCs), which act as messengers to induce the activation of T-cells.
The role of macrophages and other types of white blood cells has been well studied in scleroderma. However, the role of DCs in skin fibrosis has not been assessed.
To address this gap, a team at University of Tokyo Graduate School of Medicine and St. Marianna University School of Medicine, in Japan, investigated DCs in mice injected with the chemical bleomycin to induce skin fibrosis.
Specifically, the investigators focused on whether lacking the CD103 protein altered the role of DCs in skin fibrosis and inflammation. This cell surface protein plays a key role in determining the precise subtype that’s adopted by a DC.
Compared to controls with CD103, mice missing this protein had less skin thickening and reduced collagen levels four weeks after the bleomycin injection. In addition, the levels of growth factors that stimulate fibrosis was significantly reduced. Altogether, these results point to a vital role for DCs in skin fibrosis.
No differences were seen in the number of other immune cells in mice with or without CD103 at the peak of inflammation. However, levels of pro-inflammatory proteins were reduced in the skin of mice lacking CD103 but the amount of an anti-inflammatory protein known as interleukin-10 (IL-10) was increased. This suggests that, together with lacking CD103, increased levels of IL-10 may ease fibrosis.
The team also found higher proportions of regulatory T-cells (Tregs) in the skin of mice without CD103, compared to animals with unchanged levels of this protein. Tregs are immune cells that dampen excessive immune responses.
Then, the investigators found higher levels of an enzyme known as retinaldehyde dehydrogenase-1 (RALDH1) in mice lacking CD103 than in the controls after the injection of bleomycin. RALDPH1 is responsible for the production of retinoic acid (the active metabolite of vitamin A), which plays a critical role in the conversion of T-cells into Tregs mediated by DCs.
Using small RNA molecules to block the activity of the gene producing RALDPH1 suppressed the increased levels of Tregs in the skin and promoted skin fibrosis. This reveals that the increase in Tregs is central to the reduction of dermal fibrosis in mice lacking CD103.
The team also analyzed skin tissue isolated from scleroderma patients. Reduced numbers of DCs with RALDH1 were found in skin lesions compared to healthy controls, particularly in patients with diffuse cutaneous disease.
“These results indicate that RALDH1-dependent Treg regulation is potentially involved in the pathological tissue fibrosis of SSc [scleroderma],” the scientists wrote.
“This finding sheds new light on dermal DCs as a new therapeutic target of SSc,” they added.
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