Signaling pathway in skin cells may drive scleroderma inflammation
Study findings point to crucial molecular axis as potential treatment target
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Researchers have identified a molecular pathway in specific skin cells called keratinocytes that may be involved in inflammation and scarring in scleroderma affecting the skin.
According to data from a mouse model of the disease, loss of the protein Med1 in keratinocytes leads to more severe disease, likely by overactivating the PPAR-gamma pathway. While this pathway normally limits inflammation and scarring, its overactivation increases inflammatory signaling that may drive scleroderma progression.
These findings point to this Med1-PPAR-gamma axis as a potential treatment target in scleroderma, the scientists noted.
The results were described in the study “Deficiency of Med1 in keratinocytes augments dermal fibrosis and inflammation in scleroderma,” which was published in International Immunopharmacology.
Mice lacking Med1 in their keratinocytes developed more skin fibrosis
Scleroderma is a disorder characterized by chronic inflammation and progressive tissue scarring (fibrosis) in the skin and various organs. Studies of the disease usually focus on immune cells, which control inflammation, or on fibroblasts, the cells primarily responsible for forming scar tissue.
But immune cells and fibroblasts aren’t the only cell types that may play a role in this disease. Some data suggest that keratinocytes also may contribute to disease processes in scleroderma. Keratinocytes are the main cells that make up the outermost layer of the skin, forming a barrier that protects the body from the outside world.
The Med1 protein plays a central role in regulating the biological activity of keratinocytes under normal, healthy conditions. In this study, a team of Chinese researchers sought to determine whether Med1 in keratinocytes affects the development of scleroderma in lab models.
To find out, they used a mouse model of skin scleroderma in which a chemical called bleomycin is injected into the animal’s skin, triggering fibrosis similar to that seen in people with scleroderma. The scientists then compared scleroderma progression between mice engineered to lack Med1 specifically in their keratinocytes and unaltered mice.
They found that mice lacking Med1 in their keratinocytes developed significantly more skin fibrosis. Increased markers of skin inflammation and sustained activation of fibrosis-driving fibroblasts accompanied this uptick in scarring.
[PPAR-gamma] signaling — typically considered anti-inflammatory and anti-fibrotic — exhibits a clear pro-inflammatory effect in this context.
In subsequent experiments, the researchers found that Med1 deficiency in keratinocytes led to excessive activation of PPAR-gamma, a signaling pathway generally thought to help limit inflammation and fibrosis. This leads to increased levels of pro-inflammatory factors.
Overall, the findings indicated that in keratinocytes lacking Med1, the PPAR-gamma pathway spins into overdrive, dysregulating cell activity and ultimately leading keratinocytes to produce more pro-inflammatory signaling molecules.
“[PPAR-gamma] signaling — typically considered anti-inflammatory and anti-fibrotic — exhibits a clear pro-inflammatory effect in this context,” the researchers wrote. “This functional switch identifies Med1 as a critical regulatory node in [keratinocytes]; its loss hyperactivates [PPAR-gamma], converting it from a putative suppressor into a central driver of inflammation and fibrosis.”
Collectively, these data suggest that this Med1-PPAR-gamma signaling pathway plays a key role in scleroderma of the skin and may be a useful target for treating the disease, the researchers noted.
They cautioned, however, that targeting this pathway “presents complex challenges,” particularly since the PPAR-gamma pathway may help limit inflammation in other parts of the body. They speculated that carefully tailored approaches — such as developing PPAR-gamma-blocking agents that can be applied to the skin — may warrant further exploration.
