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The role of glial cells in multiple sclerosis disease progression

Nature Reviews Neurology volume 18, pages 237–248 (2022)Cite this article

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Abstract

Despite the development of highly effective treatments for relapsing–remitting multiple sclerosis (MS), limited progress has been made in addressing primary progressive or secondary progressive MS, both of which lead to loss of oligodendrocytes and neurons and axons, and to irreversible accumulation of disability. Neuroinflammation is central to all forms of MS. The current effective therapies for relapsing–remitting MS target the peripheral immune system; these treatments, however, have repeatedly failed in progressive MS. Greater understanding of inflammation driven by CNS-resident cells — including astrocytes and microglia — is, therefore, required to identify novel potential therapeutic opportunities. Advances in imaging, biomarker analysis and genomics suggest that microglia and astrocytes have central roles in the progressive disease process. In this Review, we provide an overview of the involvement of astrocytes and microglia at major sites of pathology in progressive MS. We discuss current and future therapeutic approaches to directly target glial cells, either to inhibit pathogenic functions or to restore homeostatic functions lost during the course of the disease. We also discuss how bidirectional communication between astrocytes and microglia needs to be considered, as therapeutic targeting of one is likely to alter the functions of the other.

Key points

  • Immune mechanisms of progressive multiple sclerosis (MS) predominantly involve cells that are resident in the CNS, leptomeninges or cerebrospinal fluid, whereas MS relapses are driven by transient infiltration of peripheral immune cells.

  • The contributions of microglia and astrocytes — resident glial cells of the CNS parenchyma — to tissue injury and repair reflect their dynamic state of activation.

  • In MS, glial cells are activated across the CNS, including expanding white matter lesions, superficial cortical grey matter, periventricular deep grey matter and the spinal cord.

  • Glial cell activation states reflect responses to the local environment (for example, injured neurons and neighbouring glia) and the external environment (for example, viruses and microbiome products).

  • Clinically applicable markers of glial cell activation include imaging (MRI and PET) and bio-assays (cell type-related proteins, microRNAs and exosomes).

  • Current therapies that affect glial function largely modulate signal transduction pathways; future directions include genetic reprogramming and/or endogenous cell replacement.

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Fig. 1: Immunohistochemical features of mixed active–inactive lesions and active lesions.
Fig. 2: Immunohistochemical features of subpial and periventricular multiple sclerosis lesions.

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Authors and Affiliations

  1. Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Québec, Canada

    Luke M. Healy, Jo Anne Stratton, Tanja Kuhlmann & Jack Antel

  2. Institute of Neuropathology, University Hospital Münster, Münster, Germany

    Tanja Kuhlmann

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  1. Luke M. Healy
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Healy, L.M., Stratton, J.A., Kuhlmann, T. et al. The role of glial cells in multiple sclerosis disease progression. Nat Rev Neurol 18, 237–248 (2022). https://doi.org/10.1038/s41582-022-00624-x

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