MicroRNA may be therapeutic target for Sjögren’s: Study
Rat study shows mimicking molecule's activity eases inflammation, scarring
A naturally occurring molecule that has the ability to regulate gene activity may represent a promising therapeutic target for Sjögren’s disease and other autoimmune conditions, according to a study.
Mimicking the activity of the molecule, miR-216a-3p, eased inflammation and scarring in a rat model of the disease. Its therapeutic effects seem to lie in its ability to inhibit the pro-inflammatory STAT1/JAK signaling pathway, preventing the activation of the immune B-cells that have been implicated in the disease.
“These results collectively suggest a potentially significant role for miR-216a-3p in the [development] of autoimmune diseases, warranting further investigation,” the researchers wrote.
The study, “miR-216a-3p alleviates primary Sjögren’s syndrome by regulating the STAT1/JAK signaling pathway,” was published in Biochemical and Biophysical Research Communications.
Sjögren’s disease is an autoimmune condition in which the immune system mistakenly attacks the body’s healthy moisture-producing glands, leading to Sjögren’s symptoms such as dry eyes and mouth.
MicroRNAs seen driving diseases
While some cases of Sjögren’s are associated with other underlying conditions — this is known as secondary Sjögren’s — the cause of primary Sjögren’s, in which the condition arises in the absence of other diseases, is not understood.
Accumulating data suggest that microRNAs (miRNAs), small strands of genetic material capable of influencing gene activity, play a role in driving autoimmune diseases such as Sjögren’s. Indeed, altered miRNA profiles have been observed in the tears of people with primary Sjögren’s.
Several miRNAs are known to influence genes involved in the JAK/STAT signaling pathway. This pathway has been linked to inflammation and activation of antibody-producing immune cells, namely B-cells, that are believed to contribute to Sjögren’s disease processes.
The researchers set out to further identify the miRNAs that might be involved in Sjögren’s, and to establish their influence on JAK/STAT signaling.
They first looked at gene activity data sets from people with and without Sjögren’s, finding gene activity changes particularly associated with inflammatory responses. The most substantially altered one was the JAK/STAT gene STAT1, which had elevated activity in Sjögren’s.
The scientists then identified a number of miRNAs that might work upstream of STAT1 to regulate its activity, with miR-216a-3p being the one predicted to have the greatest effect.
miR-216a-3p activity was lower in glandular tissues of people with primary Sjögren’s relative to people without it, while STAT1 activity was higher. Blood and salivary gland tissue analyses showed signs of elevated inflammation in people with primary Sjögren’s.
To further explore the role of miR-216a-3p, the scientists treated a rat model of Sjögren’s with compounds to either mimic or inhibit miR-216a-3p.
Treatment with the miR-216a-3p mimic led to significant reductions in inflammation and scarring within the salivary glands and helped to increase saliva flow rate. Inflammation and scarring were increased, while salivary flow rate was decreased, with the miR-216a-3p inhibitor.
As in humans, miR-216a-3p activity was reduced and STAT1 activity was increased in salivary gland tissue from the rat model. When the rats were treated with the miR-216a-3p mimic, STAT1 activity went down, as did the levels of several pro-inflammatory proteins in the blood. Again, the reverse was true with the miR-216a-3p inhibitor.
Further experiments showed that the miR-216a-3p mimic appeared to inhibit the activation of JAK/STAT signaling to prevent the overactivation of B-cells.
“This finding not only reveals the potential role of miR-216a-3p in regulating B cell function but also provides a new therapeutic target for [primary Sjögren’s],” the researchers wrote.
The scientists said future research will focus more on how miR-216a-3p influences B-cell signaling pathways, and will further evaluate its therapeutic potential.
“This will not only help deepen our understanding of the [development of primary Sjögren’s] but may also offer new therapeutic insights for other autoimmune diseases,” the team wrote.
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