http://embomolmed.embopress.org/content ... .201809369
Microglia P2X4 receptors as pharmacological targets for demyelinating diseases
Multiple sclerosis (MS) is a chronic inflammatory disease of the brain and the spinal cord characterized by infiltration of immune cells, gliosis and axonal degeneration (Dendrou et al, 2015). Experimental allergic encephalomyelitis (EAE) replicates the typical inflammatory changes in demyelinating lesions of MS and is generally acknowledged as a useful experimental model.
The inflammatory infiltrate in AS and EAE is predominantly characterized by mononuclear cells such as microglia, macrophages and lymphocytes. Activation of microglia and blood‐derived macrophages is a main pathogenic mechanism responsible for lymphocyte recruitment and activation, as well as for axonal damage and neurodegeneration. However, a more recent view holds that microglia can also be beneficial for the recovery process in MS by accelerating the removal of myelin debris, by providing neurotrophic factors and by promoting immunosuppression (Miron et al, 2013). Beneficial effects of microglia depend on its differentiation towards an anti‐inflammatory phenotype.
Microglia, like tissue macrophages, is thought to be present in two alternative activation states, pro‐inflammatory type I or classically activated (M1), and anti‐inflammatory type II, or alternatively activated (M2). Nowadays, this distinction in microglia is believed to be not as clear‐cut as in macrophages, since microglia activation is a highly dynamic and plastic process where the transition from one activation state to the other occurs along a continuum of functional changes (Wolf et al, 2017). Nevertheless, the identification of a pro‐inflammatory or an anti‐inflammatory microglia phenotype offers a useful operational framework for decoding microglia responses and understanding its participation in disease processes.
Microglia activation and graded differentiation towards a pro‐inflammatory or anti‐inflammatory phenotype are driven by factors released from injured nerve cells (damage‐associated molecular patterns, DAMPs) or pathogen‐derived factors (pathogen‐associated molecular patterns, PAMPs), but receptors and intracellular pathways involved are poorly understood. It would be useful to be able to direct microglia differentiation towards one or the other differentiation pathway, but how this might be achieved is as yet unknown. This is an important issue because while pro‐inflammatory microglia is thought to be a prime culprit of immune cell recruitment and brain damage, anti‐inflammatory microglia releases neuroprotective factors, dampens immunity and supports nerve cell recovery.
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