MACROPHAGES, microRNA-155 & MULTIPLE SCLEROSIS
Macrophage infiltration in CNS
The inflammatory disease primarily studied currently by the McCoy lab is the most common neurological disorder affecting young adults- multiple sclerosis (MS).
There is no single cause for MS, with reasons ranging from genetic vulnerability to environmental factors. However, it has been conclusively shown that the symptoms and pathology presented by MS patients begin due to infiltration of immune cells called macrophages from periphery traversing the blood-brain barrier into the Central Nervous System (CNS).
This infiltration leads to symptoms starting with inflammation, resulting in demyelination and finally axonal degeneration.
The macrophages that infiltrate the CNS are termed classically activated or M1 macrophages, that are shown to be located within MS active lesions and release a range of pro-inflammatory cytokines like TNF-a, IL-1b, and IL-6 as well as chemokines (e.g. CCL2, CXCL10). On the contrary, alternatively activated or M2 macrophages are shown to be present in the later stages of the disease, releasing anti-inflammatory cytokines and are involved in tissue repair. This means that switching and maintaining the macrophages in an M2 state could hold great therapeutic potential for treatment of inflammatory conditions. However, the mechanisms that are responsible for macrophage polarization are mostly unknown.
MicroRNAs, such as miR-155, are a class of non-coding RNA molecules involved in regulation of gene expression at the post-transcriptional level. They have been shown to function as mediators in many CNS biological processes including development, plasticity, and neurodegeneration. microRNAs can repress translation of their target mRNAs or direct the mRNA itself for degradation; a single miRNA can regulate post-transcriptional expression of many genes and hence, they can coordinate complex gene expression pathways depending on cellular context.
Data from the McCoy lab has shown that miR-155 is an essential mediator of the M1 pro-inflammatory response in macrophages. Basal levels of miR-155 in macrophages are very low but can be potently induced by agonists required for M1 polarization such as LPS and IFN-y. Sustained overexpression of miR-155 in human macrophages increase levels of pro-inflammatory cytokine secretions. Last but not least, miR-155 levels have been identified as being elevated in monocyte-derived macrophages isolated from MS patient blood samples.
We hence hypothesize that miR-155 is a key therapeutic target in macrophages, and that inhibition of miR-155 will maintain macrophages in an M2 phenotype reducing inflammation and alleviating disease progression.
The McCoy strategic research programme has four overarching aims. These are designed to fully understand how miR-155 controls macrophage mechanisms in order to translate this concept in MS mouse models with the ultimate aim to design a novel therapeutic: