Researchers from China proposed a new way in which the circular RNA circ_0000518 may play a role in the progression of multiple sclerosis (MS). Circular RNAs work as microRNA modulators and are often involved in the progression of diseases such as cancer.
According to the authors of the study published in Neuroscience, targeting circ_0000518 could be a novel therapeutic approach for MS.
It is already known that circ_0000518 is overexpressed in the cerebrospinal fluid (CSF) and peripheral blood of patients with MS. Here, a team of researchers from Shaanxi Provincial People’s Hospital and the Second Hospital of Hebei Medical University in China explored the regulatory mechanism of circ_0000518 in MS progression.
First, the team induced inflammatory responses in human microglial cells grown in culture by treating them with LPS. They then treated the cells with the short hairpin RNA against hsa_circ_0000518, which increases circ_0000518 expression.
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They found that higher circ_0000518 expression increased apoptosis and oxidative stress. It also increased the expression of markers of the M1 phenotype, or classically activated macrophages, and decreased that of markers of M2 phenotype, or the alternatively activated macrophages. Finally, interfering with circ_0000518 expression reversed the effect of LPS on these cells.
The researchers also found that the expression of the RNA-binding protein FUS was increased in LPS-treated cells. “Interfering with FUS expression reduced LPS triggered apoptosis and oxidative stress, decreased M1 phenotype marker expression, and promoted M2 phenotype marker expression,” they wrote.
Finally, the team conducted experiments in a mouse model of autoimmune encephalomyelitis and showed that circ_0000518 knockdown reduced FUS expression in the brain and spinal cord, reduced neurological scores, and alleviated the infiltration of inflammatory cells to the central nervous system.
These findings suggest that circ_0000518 may be a potential target for the treatment of MS.
Jiang F, Liu X, Cui X, et al. Circ_0000518 promotes macrophage/microglia M1 polarization via the FUS/CaMKKβ/AMPK pathway to aggravate multiple sclerosis. Neuroscience. 2021;14:S0306-4522(21)00636-9. doi:10.1016/j.neuroscience.2021.12.012