The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells

Abstract

Background: Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS's immune landscape.

Main body: In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs' pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs' differentiation and immune functions.

Conclusion: We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs' pro-myelinating and immune-modulatory functions.

Keywords: Demyelination; Immune-modulation; Immune-suppression; Multiple sclerosis; Myelin; Neurodegeneration; Neuroinflammation; Oligodendrocyte progenitor cell; Regeneration; Remyelination.

Fig. 1

A multi-dimensional view: OPCs’ immune-modulation and pro-myelinating roles. Under inflammatory conditions, the CNS is abundant with detrimental inflammatory products such as IFNγ and myelin debris. These products suppress OPC differentiation while stimulating their immune activities, including phagocytosis, antigen presentation, and cytokine secretion [10, 104, 129, 130] (left upper panel). OPCs fail to differentiate into mature myelinating oligodendrocytes in environments with limited inflammation or anti-inflammatory conditions. Concurrently, their immune functions, such as antigen presentation, T-cell activation, and cytokine secretion, are compromised [97, 104, 131] (left lower panel). Pushing OPCs towards differentiation, combined with non-specific immune suppression, enables OPCs to differentiate into mature oligodendrocytes. However, this fails to ameliorate the disease burden in the Biozzi chronic EAE model (it also did not promote OPC migration to the areas of axonal loss). Additionally, their immune activities are dampened, preventing them from performing their immune-related roles [, –134] (right lower panel). Successful remyelination relies on a well-regulated immune response, spatially and temporally controlled and of appropriate intensity [135, 136]. OPC must fulfill both roles: the regenerative and immune functions. OPCs are tasked with balancing both regenerative and immune functions. TNFα and oligodendroglial TNFR2 exemplify agents that harmonize the regenerative and immunological duties of OPCs within the inflamed CNS, endorsing both differentiation and immune-modulation [94, 97, 104, 111, 137] (right upper panel)