Researchers have discovered that plasmacytoid dendritic cells (pDCs) contribute to the skin scarring in scleroderma, making them a possible target for treating the disease.
The study, “Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8,” was published in the journal Science Translational Medicine.
Although a combination of inflammation and scarring, or fibrosis, characterize all forms of scleroderma, the link between these two processes has not been well understood.
PDCs are a type of immune cell that detect viruses and bacteria through a family of receptors called Toll-like receptors (TLR). In response to infections, pDCs promote immune responses and inflammation by producing molecules called type I interferons (IFNs).
Although these pDCs-dependent responses are also implicated in the development of autoimmune diseases, their role in fibrosis was unclear.
A team of researchers at the Hospital for Special Surgery (HSS) in New York showed that pDCs infiltrate the skin of patients with scleroderma, contributing to the development of scarring.
PDCs were found to be chronically activated, producing high levels of IFNs and CXCL4, a biomarker of scleroderma. The increased secretion of CXCL4 was due to the unusual presence of Toll-like receptor 8 (TLR8) in the pDCs of scleroderma patients. This receptor is not found in pDCs of healthy people.
Eliminating pDCs in a mouse model of scleroderma not only prevented the disease, but also reversed scarring. Conversely, mice genetically modified to produce too much TLR8 showed aggravated stages of scleroderma, with pDCs being recruited to the scarred skin.
The data indicated that TLR8 is responsible for the increased activity of pDCs and fibrosis.
“Plasmacytoid dendritic cells are known to be activated in many other rheumatic conditions, including lupus,” Franck Barrat, the study’s senior author, said in a press release. “But our findings suggest that they participate in both establishing and maintaining fibrosis in the skin as well. This is a very interesting finding as it opens new ways to tackle this condition.”
The elimination of pDCs “using depleting antibodies or attenuating pDC function could be a novel approach to treat SSc [Systemic sclerosis] patients,” the team wrote.
The study is a step further in understanding the mechanisms behind scleroderma, and they may lead to the development of new therapies. Since drug companies are already trying to develop strategies to eliminate pDCs as a way of treating other diseases, Barrat hopes that “a better understanding of the role pDCs play in fibrosis will open up the possibility of repurposing existing drugs to treat patients with scleroderma.”