Immune Cell microRNAs Are Potential MS Biomarkers, Study Suggests

Altered levels of molecules important for cell regulation — called microRNAs — have been found in specific immune cells isolated from the blood of people with multiple sclerosis (MS), a study reveals.

These immune cells, called monocytes, transform into macrophage cells, which is a cell type involved in MS-related tissue damage. The study suggests that the pattern of microRNAs in monocytes may be a new MS biomarker to help monitor disease progression. 

The study, “Immune and central nervous system-related miRNAs expression profiling in monocytes of multiple sclerosis patients,” was published in the journal Nature Scientific Reports. 

MS is caused by the immune system attacking the protective coating around nerve cells, called myelin, leading to inflammation and further damage. Immune cells known as macrophages are commonly found in close proximity to the areas of myelin damage (lesions) and are involved in MS-related tissue damage.

Macrophage cells are important in defending against bacteria and viruses, and thus have a pro-inflammatory role. But macrophages also can have the opposite function — by regulating the end of inflammation (anti-inflammatory role) and the repair of damaged tissues. 

These cells start out as a blood cell type called monocyte and transform into macrophages as they move into the tissue to fight infections or initiate repair. Macrophages that are either pro-inflammatory or anti-inflammatory are created by a process known as macrophage polarization. 

A variety of biomarkers are currently used to identify the state of macrophage polarization.

Recently, research on potential MS biomarkers has focused on molecules that can be isolated from blood and other bodily fluids called microRNAs (miRNAs) — short stretches of genetic material that regulate gene activity and an increase or decrease in the production of proteins within a cell. 

A variety of potential miRNA biomarkers have been isolated from MS patients, with some stimulating the transformation of monocyte cells into pro-inflammatory macrophages and others triggering the anti-inflammatory state. 

“However, how the phenotype of human monocytes evolves in the course of MS is largely unknown,” the researchers wrote.

To bridge this gap in knowledge, researchers at the University of Foggia, along with colleagues at the CNR Institute of Neuroscience and the San Raffaele Scientific Institute, all in Italy, conducted an exploratory study to measure the levels of eight confirmed MS-related miRNA biomarkers in monocyte cells isolated from the blood of 29 people with MS: 21 with relapsing-remitting MS (RRMS), and eight with primary progressive MS (PPMS).

All patients were in remission without active disease, and they had not received disease-modifying therapies three months before the study. A group of 16 healthy individuals was included as controls.

The miRNAs analyzed were: miR-223, miR-146a, miR-155, miR-181, miR-23a, miR-124, miR-125a, and miR-30c. All these miRNAs are involved in macrophage polarization.

Results showed that the levels of all eight miRNAs tested were significantly altered in monocyte cells isolated from people with MS, compared to healthy controls. 

Of these, five miRNAs with anti-inflammatory functions had significantly higher levels — miR-146a, miR-223, miR-125a, miR-30c, and miR-23a — in people with RRMS or PPMS. Whereas, one pro-inflammatory microRNA (miR-155) was found in significantly lower levels in these patients, compared to controls.

“These changes may indicate the attempt of monocytes to counteract neuroinflammation,” the researchers wrote.

The team also analyzed the state of macrophage polarization by determining the levels of four specific RNAs that are translated into proteins (RNA is the molecule that carries the instructions for protein production using DNA as a template).

Overall, there were no differences in RNA levels for the pro-inflammatory markers interleukin-1-beta (IL-1-beta) and tumor necrosis factor-alpha (TNF-alpha), with the exception of a slight reduction in TNF-alpha in PPMS patients compared to controls.

Significantly lower levels of the anti-inflammatory interleukin-10 RNA were found in those with PPMS, while there was a significantly higher amount of anti-inflammatory chitinase 3 like 1 (CHI3L1) RNA in PPMS patients, compared to RRMS patients and control subjects.

“In conclusion, our results show that miRNAs with anti-inflammatory functions, which promote pro-regenerative [macrophage] polarization, are increased in MS patients, while miR-155, the prototypical pro-inflammatory miRNA is downregulated in the same patients. These changes may reflect the attempt of monocytes to establish an anti-inflammatory/pro-regenerative response in MS,” the researchers wrote.

The team suggested that such patterns of miRNAs expression “may help to define the monocytes/macrophages activation state in RRMS and PPMS patients, representing possible disease biomarkers.” Furthermore, “understanding how monocyte polarization evolves during MS could not only provide novel biomarkers to monitor the disease but it could also provide novel therapeutic opportunities,” they added.