Investigating novel metabolites on the regulation of microRNAs for the treatment of Multiple Sclerosis

The study of metabolites has yielded new insights into the mechanisms that mediate immune cell function. Recent advances have highlighted that in addition to regulating energy states in a cell, metabolites can have a major impact on immune cells such as macrophages. For example, succinate, an intermediate metabolite of the Krebs’ cycle, has been shown to accumulate and act as a potent signal inducing the inflammatory state of macrophages (1). On the other hand, another metabolite called itaconate can act as an anti-inflammatory molecule, counteracting the actions of succinate, through the inhibition of pro-inflammatory signals and reactive oxygen species (2). Interestingly, succinate has been shown to drive an inflammatory state within the central nervous system of a Multiple Sclerosis (MS) disease model (3), whereas the administration of itaconate can reverse this effect (2). This suggests that the repurposing of metabolites holds huge potential as anti-inflammatory agents in many diseases including MS.

The discovery of microRNAs has led to a very exciting and rapidly growing area of research. microRNAs are extremely small RNA molecules that play a critical role in normal immune cell function. However, for reasons that we don’t fully understand, microRNAs are also dysregulated in multiple inflammatory diseases. MicroRNA (miR)-155, a pro-inflammatory microRNA, has been particularly implicated in MS (4). Elevated levels of miR-155 are found in the serum and brain lesions of MS patients (5), while data from Dr McCoy’s laboratory has identified that miR-155 is particularly elevated in macrophages that infiltrate and cross the blood brain barrier in a MS disease model. miR-155 activation results in the release of pro-inflammatory cytokines and toxic mediators and contribute to the damage observed in MS brain pathology (4). Significantly, we have shown for the first time that inhibition of miR-155 in macrophages can change their phenotype to an anti-inflammatory state that could potentially promote tissue repair (6, 7). Thus, inhibition of miR-155 in macrophages could offer a novel therapeutic approach for the treatment of MS.

This PhD project will focus on examining a range of metabolites and assessing their impact on miR-155 expression, macrophage metabolism and plasticity, with the aim that a metabolite will be selected for its efficacy in the MS disease model. The PhD candidate will be based in Dr Claire McCoy’s laboratory at RCSI who leads a research team investigating the impact of miR-155 on MS disease pathology. She was the recent recipient of a prestigious President of Ireland Future Research Leader Award. Prof Luke O’Neill will act as a co-supervisor, he is a world leader and expert in Immunometabolism, publishing frequently in Nature, Cell and Science. The successful candidate will have opportunities to engage with Prof O’Neill’s lab at Trinity College Dublin, as well as undertake industry secondments associated with his research programme