An international team of researchers from the University of Colorado’s (CU) Anschutz Medical Campus’s School of Medicine, in collaboration with the University of Cambridge, has revealed a molecular signature that plays a role in activating immune cells in neurological diseases, including progressive multiple sclerosis (MS).
Published in the journal Nature, the study explains how microglia uses the mitochondria, the energy generator of the cell, to determine a persistent state of activation that can cause irreversible neuronal damage and neurodegeneration.
Affecting more than two million people worldwide, MS occurs when the body’s own immune system mistakenly attacks and damages myelin, the protective sheath around nerve fibres, causing damage to the brain and spinal cord, otherwise known as lesions.
Microglia, found around the lesion, are immune cells of the brain that respond to pathogens and damage. However, in MS, microglia can cause damage by being persistently activated.
Researchers used mouse models of experimental autoimmune encephalomyelitis, a collection of related conditions in which the body’s immune system attacks the brain, which refers to acute to subacute progressive inflammation of the brain.
The team discovered a molecular pathway involving mitochondrial complex I (CI) activity, reverse electron transport (RET) and the production of reactive oxygen species to reveal the metabolic underpinnings of inflammation in chronic neurological diseases.
The study suggests that inhibiting CI in microglia in chronic inflammatory central nervous system disorders, including progressive MS, could be a strong approach to tackling these conditions.
Additionally, researchers blocked CI in pro-inflammatory microglia, which led to neuroprotection and offers the potential to develop targeted therapies that modulate microglial activation.
Professor Stefano Pluchino from the University of Cambridge said: “Our work unravels a previously unrecognised aspect of microglial activation in progressive MS” and “may have identified a promising therapeutic strategy… in progressive MS and potentially other neurodegenerative diseases”.
Angelo D’Alessandro, professor at the CU School of Medicine, said: “Our data shows that immune cells from this model are characterised by elevated markers of oxidant stress and dysfunctional mitochondrial metabolism in vivo, paving the way for studies on the efficacy of interventions aimed at blocking a novel mechanism of mitochondrial dysfunction, called RET.”