Research Implicates MicroRNA in Primary Sjögren’s Syndrome Eye Inflammation

A small RNA molecule may help to drive inflammation in the eyes of people with primary Sjögren’s syndrome (pSS), a new study reports. The findings imply that this molecule, called miR-744-5p, may be a therapeutic target for pSS.

The study, “miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome,” was published in the journal Nature Scientific Reports.

Dry eyes are one of the characteristic symptoms of pSS, and it is widely agreed that this symptom is caused by overactive inflammation in and around the tear ducts. However, the exact mechanisms driving this inflammation remain an open area of investigation.

Previous studies have shown that an imbalance in the activity of small RNAs — also called microRNAs (miRNAs), which are tiny RNA molecules that can interfere with the activity of genes and protein production — is associated with inflammatory autoimmune conditions, including pSS.

A team led by researchers in Ireland now investigated in more detail the role of microRNAs in pSS eye inflammation.

Researchers analyzed miRNA expression in eye cells taken from 20 people with pSS (75% female, average age 57.9 years), all of whom were experiencing dry eyes. These were compared to miRNAs in eye cells from 11 people without pSS.

Numerous miRNAs were found to be significantly altered in pSS eye cells. The researchers focused on one called miR-744-5p, which was expressed at significantly higher levels in eye cells from people with pSS.

This miRNA was of interest because it previously has been implicated in inflammation and suggested to play a role in another autoimmune disease,  lupus. Furthermore, analysis of the sequence of miR-744-5p suggested that it could target the gene PELI3, which provides instructions for making a protein called Pellino 3. Pellino 3 is known to limit inflammation.

The researchers hypothesized that the high levels of miR-744-5p seen in pSS could drive eye inflammation by reducing the amount of Pellino 3. Moreover, PELI3 activity was significantly reduced in eye cells from people with pSS, lending credence to their hypothesis.

To test this idea, researchers used various molecular biology techniques to increase or decrease the activity of miR-744-5p in human eye cells in a laboratory setting. They found that when miR-744-5p activity was increased, the amount of Pellino 3 decreased, and vice versa.

Furthermore, the team confirmed the sequence in the PELI3 gene that miR-744-5p recognizes and binds to, which exerted its inhibitory activity.

“Taken together, our data demonstrates that PELI3 is both a novel and direct target of miR-744-5p,” the researchers wrote.

The team then tested whether blocking miR-744-5p — and, by extension, increasing Pellino 3 levels — affected inflammation. They found that blocking miR-744-5p significantly reduced the expression of inflammatory molecules like chemokine 10 (CXCL10).

“Overall these studies reveal a novel role for miR-744-5p in mediating ocular [eye] inflammation via Pellino3 expression in [pSS] patients,” the researchers wrote.

It is worth emphasizing that most of these experiments were done using cells in a laboratory setting. As such, further research is needed to determine whether the same processes are at work in human disease.

“This is a first step toward a potential new treatment, and much more pre-clinical testing is needed before we can develop it into something that is ready for patients,” Joan Ni Gabhann-Dromgoole, PhD, said in a press release. She is a lecturer at the Royal College of Surgeons in Ireland, and the study’s co-author.

“However, our research provides the opportunity to possibly treat the root cause of the disease rather than just the symptoms,” she concluded.