Central nervous system demyelinating diseases: glial cells at the hub of pathology

Abstract

Inflammatory demyelinating diseases (IDDs) are among the main causes of inflammatory and neurodegenerative injury of the central nervous system (CNS) in young adult patients. Of these, multiple sclerosis (MS) is the most frequent and studied, as it affects about a million people in the USA alone. The understanding of the mechanisms underlying their pathology has been advancing, although there are still no highly effective disease-modifying treatments for the progressive symptoms and disability in the late stages of disease. Among these mechanisms, the action of glial cells upon lesion and regeneration has become a prominent research topic, helped not only by the discovery of glia as targets of autoantibodies, but also by their role on CNS homeostasis and neuroinflammation. In the present article, we discuss the participation of glial cells in IDDs, as well as their association with demyelination and synaptic dysfunction throughout the course of the disease and in experimental models, with a focus on MS phenotypes. Further, we discuss the involvement of microglia and astrocytes in lesion formation and organization, remyelination, synaptic induction and pruning through different signaling pathways. We argue that evidence of the several glia-mediated mechanisms in the course of CNS demyelinating diseases supports glial cells as viable targets for therapy development.

How Early Is Early Multiple Sclerosis?

“…Notwithstanding the current debate on the sequence of events taking place at the onset of MS pathology, neuroscientists believed for decades that neuroinflammation starts with the crossing of the blood–brain barrier (BBB) by CD4+ T helper (Th) cells and B cells that enter the CNS due to a disruption in the BBB and recognize myelin-specific antigens, which they present to Th cells and trigger an inflammatory response [ 63 , 64 ]. The inflammatory response initiates with the release of pro-inflammatory cytokines and chemokines, which lead to the recruitment of resident microglia, as well as macrophages, CD8+ cells, and astrocytes.…”

“…The inflammatory response initiates with the release of pro-inflammatory cytokines and chemokines, which lead to the recruitment of resident microglia, as well as macrophages, CD8+ cells, and astrocytes. The accumulation of these cells leads to the formation of an active lesion [ 64 , 65 ].…”

“…Although the sequence of events in the pathology of the disease is not definite, adaptive immune cells from the periphery cross the BBB and enter the CNS [ 64 ]. OCBs are mainly IgGs produced by clonally expanded B cells intrathecally [ 71 ].…”

Phage Interactions with the Nervous System in Health and Disease

“…Autoimmune disorders of the nervous system (e.g., inflammatory demyelinating diseases, myasthenia gravis, etc.) pose a significant medical challenge as their treatment is not always satisfactory while side effects of currently available therapy may be serious and sometimes life-threatening [ 184 , 185 ]. Therefore, in those clinical settings one could envisage the potential therapeutic action of selected phages with proven anti-inflammatory and immunosuppressive activity and a virtual lack of side effects [ 186 ].…”