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Molecular mechanisms identified in chronic skin inflammation

Researchers in Vienna have identified new molecular mechanisms that cause skin inflammation in conditions such as atopic dermatitis (AD) and psoriasis. They say that identifying these mechanisms could provide starting points for the development of new therapies.

The study showed the first in vivo evidence for a pro-inflammatory role of the multifunctional adapter protein, Sequestosome 1/p62, in the skin. This evidence suggests that p62-dependent signalling pathways may be promising therapeutic targets to improve the skin manifestations of AD and possibly psoriasis. The study was published online ahead of print in the Journal of Allergy and Clinical Immunology (Mar. 3, 2021),

Using patient samples and animal models, the team of researchers from the University Clinic for Dermatology and the Clinical Institute for Laboratory Medicine at MedUni Vienna was able to show p62 influences the inflammatory changes in the diseased epidermis. Further, the researchers demonstrated that inhibiting p62 leads to an alleviation of chronic inflammation.

“For this purpose, AD-like skin lesions were induced by genetic inactivation of a certain gene, called JunB, in keratinocytes—this is the type of cell mainly found in the epidermiswhich led to an increase in the expression of p62 in the skin of mice,” said Erwin Wagner, PhD, in a press release. Dr. Wagner, lead author of the study, is the genes and disease group leader at the University Clinic for Dermatology and the Clinical Institute for Laboratory Medicine at MedUni Vienna.

The contribution of p62 to pathological changes was then determined by the additional genetic inactivation of p62, the study’s authors wrote.

Results showed the loss of p62 reduced skin damage, suggesting that the inhibition of p62-dependent signals could improve the clinical picture of AD and possibly other skin diseases such as psoriasis.

Investigators were also able to detect increased amounts of p62 in skin sections from patients with AD and psoriasis. Further investigation showed the inactivation of p62 normalized the altered differentiation of epidermal keratinocytes, reduced the thickening of the epidermis and decreased the infiltration of immune cells.

“The visible skin lesions were significantly reduced, as was the circulating immunoglobulin E [IgE] in the blood,” said Dr. Wagner of the results.

High IgE levels are a typical characteristic of AD patients. At the molecular level, p62 activates certain signalling pathways that play a major role in inflammatory processes. In the absence of p62 or by a therapeutic blockade, these signalling pathways are not activated, which underlines the important role of p62 in AD-like inflammation, according to the study’s authors.

“These results provide the first in vivo evidence for an inflammatory role of p62 in the skin and suggest that p62-dependent signalling pathways are promising therapeutic targets for ameliorating the skin manifestations of AD, and possibly also psoriasis,” Dr. Wagner concluded.

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