A European research team this month published data in PLoS One suggesting that down-regulation of a specific microRNA, miR-203, is involved in the pathogenesis of psoriasis.
According to Karolinska Institutet researcher and senior author Andor Pivarcsi, this is the first time an miRNA has been closely linked to any inflammatory condition and the finding could help set the stage for new treatment options for the skin disorder.
In the study, investigators from the Karolinska Institutet, the Finnish Institute of Occupational Health, and Heinrich-Heine University aimed to identify miRNAs that play a role in psoriasis by comparing miRNA expression profiles in skin samples from healthy patients to those with psoriasis and atopic eczema, an unrelated inflammatory skin disorder.
“In the past, there were many investigations [including genetic, genomic, and proteomic studies] trying to find some explanation for these [skin] diseases,” Pivarcsi told RNAi News this week. And while hundreds of genes have been associated with the conditions, “we speculated that there might be some master switches that are regulating these differentially expressed genes.”
Since individual miRNAs can regulate multiple genes, “we thought it might be possible that the genes are dysregulated in these diseases” by miRNAs, he said.
Microarray analyses revealed that there are miRNAs specifically up-regulated in psoriasis, namely miR-203; that there are miRNAs with increased expression in both psoriasis and atopic eczema, including miR-21; and that certain miRNAs are specifically down-regulated in psoriasis, including miR-99b.
Additionally, the investigators found that there are miRNAs, specifically miR-122a, uniformly down-regulated in both skin diseases as compared to healthy skin.
To confirm the results obtained by microarray profiling, the researchers performed quantitative real-time PCR analysis of miR-203, miR-146a, miR-21, and miR-125b expression on RNA samples obtained from lesional skin of patients with psoriasis, healthy skin, or atopic eczema lesions,” the team wrote in PLoS One.
“In accordance with the microarray data, quantitative real-time PCR results showed significantly increased miR-203 levels in psoriasis skin when compared with healthy skin,” they wrote. “Moreover, miR-203 was expressed at a significantly higher level in psoriasis than in atopic eczema skin specimen.”
There was no significant up-regulation of miR-203 in atopic eczema skin samples compared with healthy skin, while a significant over-expression of miR-146a was observed in psoriatic lesional skin but not in atopic eczema lesions when compared with healthy skin, the authors added.
“The psoriasis-specific overexpression of miR-203 and miR-146 suggests that they may play specific roles in the pathogenesis of psoriasis and not only a general role in skin inflammation,” they wrote.
Additional experimentation showed that miR-21, unlike miR-203 or miR-146, was significantly up-regulated both in psoriasis and atopic eczema. Meanwhile, miR-125b was significantly decreased in both psoriasis and atopic eczema samples.
“Taken together, psoriasis is characterized by a distinct miRNA expression profile in comparison with healthy skin or with atopic eczema,” the researchers noted.
In order to gain additional insights into the psoriasis-associated miRNAs, the researchers then examined the expression of miR-203 and other miRNAs in skin and in a panel of 20 additional human organs obtained from healthy individuals.
“The psoriasis-specific overexpression of miR-203 and miR-146 suggests that they may play specific roles in the pathogenesis of psoriasis and not only a general role in skin inflammation.”
They found that miR-203 was expressed at levels more than 100 times higher in skin than most other organs, and that it showed an expression profile highly specific to keratinocytes, which are “active participants in the formation of psoriasis plaques,” versus other skin cell types. By comparison, miR-146a was detected in all organs studied.
“This observation suggests a role for [miR-203] in keratinocyte functions in healthy skin, as well as in psoriasis,” the research team wrote.
“The up-regulation of miR-203 in psoriatic plaques was concurrent with the down-regulation of an evolutionary conserved target of miR-203, suppressor of cytokine signaling 3, which is involved in inflammatory responses and keratinocyte functions,” they added. “Our results suggest that microRNA deregulation is involved in the pathogenesis of psoriasis and contributes to the dysfunction of the cross talk between resident and infiltrating cells,” which is believed to be the root of the disease.
Pivarcsi said that he and his colleagues are now conducting “in vitro experiments trying to modulate the expression of miR-203 in skin cells. We are transfecting skin cells with microRNA precursors and microRNA inhibitors and investigating how the biological function of the skin cells — like cell proliferation and differentiation, which are two processes altered in psoriasis — changes.”
“We are thinking also of [doing work] in animal models, and are building a collaboration … to get some murine disease models and take the next step” to in vivo testing, he said.
In the end, Pivarcsi said he hopes his work will lead to the development of new therapies for psoriasis, perhaps miRNA-targeted ones delivered transdermally.
“But of course … we are very far from developing drugs,” he cautioned. “We are at the level of the initial observation, but this is the direction we would like to go.”