How are the brain’s immune cells regulated?
Microglia are a type of immune cell found exclusively in the brain and spinal cord. In addition to their primary function of immune surveillance, microglia also play a vital role in supporting nerve cells and refining the connections between nerve cells. Studies focusing on microglia in recent decades have begun to identify these cells as essential in outcomes of CNS disease.
Microglia, the immune cell of the CNS, have the ability to assume neurodegenerative or neuroprotective phenotypes. Neuroprotective microglia can promote remyelination and are a potential therapeutic target in multiple sclerosis (MS). As most studies of miRNAs assess mixed tissue samples, there is little information available regarding the cell specific roles of miRNAs in human disease. We have taken an innovative approach and generated a microglial specific miRNA and mRNA data set across a range of developmental stages in humans and mice. This dataset, which is unique to our team, has enabled us to focus on miRNAs which have high clinical relevance based on the gene networks they regulate and their potential to control the inflammatory phenotype of microglia. The use of both human and mouse data sets ensures the translatability of miRNA candidates through our human dataset, while simultaneously allowing us to back-translate and use pre-clinical animal models to verify the efficacy of our candidate miRNA.
The comparison of our mouse and human miRNA has identified many highly promising miRNA candidates. We have shortlisted miRNA enriched in both human and mouse microglia, which have promising functional roles based on the literature. miRNAs can either be therapeutic targets (silenced with antagomirs) or direct therapeutics (miRNA-mimics). Both strategies have high therapeutic relevance and are not necessarily exclusive. Maximal therapeutic benefit may come from the combined use of antagomirs and mimics to increase “reparative” miRNAs while decreasing “degenerative” miRNAs. The overall aim of the current study is to identify the miRNAs that serve as master regulators of microglial functions that will promote remyelination thereby prioritising the best therapeutic targets for future translational work.
Alexander D. Walsh, Sarrabeth Stone, Andrea Aprico, Trevor J. Kilpatrick, Brendan A. Ansell* and Michele D. Binder* Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system doi: https://doi.org/10.1101/2022.07.12.499835
Walsh, A., Nguyen, L.T.T. and Binder, M.D. (2021) miRNAs in microglia: Important players in multiple sclerosis pathology. ASN Neuro 13:1-23