Microglia: The Missing Link to Decipher and Therapeutically Control MS Progression?

Abstract

Therapeutically controlling chronic progression in multiple sclerosis (MS) remains a major challenge. MS progression is defined as a steady loss of parenchymal and functional integrity of the central nervous system (CNS), occurring independent of relapses or focal, magnetic resonance imaging (MRI)-detectable inflammatory lesions. While it clinically surfaces in primary or secondary progressive MS, it is assumed to be an integral component of MS from the very beginning. The exact mechanisms causing progression are still unknown, although evolving evidence suggests that they may substantially differ from those driving relapse biology. To date, progression is assumed to be caused by an interplay of CNS-resident cells and CNS-trapped hematopoietic cells. On the CNS-resident cell side, microglia that are phenotypically and functionally related to cells of the monocyte/macrophage lineage may play a key role. Microglia function is highly transformable. Depending on their molecular signature, microglia can trigger neurotoxic pathways leading to neurodegeneration, or alternatively exert important roles in promoting neuroprotection, downregulation of inflammation, and stimulation of repair. Accordingly, to understand and to possibly alter the role of microglial activation during MS disease progression may provide a unique opportunity for the development of suitable, more effective therapeutics. This review focuses on the current understanding of the role of microglia during disease progression of MS and discusses possible targets for therapeutic intervention.

Keywords: disease progression; microglia; multiple sclerosis; targets; therapy.

Figure 1

Schematic overview of microglia polarization in multiple sclerosis (MS). During disease progression, a central nervous system (CNS) compartmentalized milieu generated by pro-inflammatory B and T cells as well as CNS resident cells leads to a reactive phenotype of microglia with neuroinflammatory properties. By secreting cytokines and upregulation of particular cell surface molecules, the phenotype triggers oligodendrocyte damage, resulting in demyelination, axonal damage, and neuronal loss. On the other side, microglia have important physiological functions in maintaining tissue homeostasis, including clearance of debris, resulting in neuroprotection. Candidate drugs for treatment of MS progression may either inhibit pro-inflammatory (S1P, BTK, CSF-1R) or enhance anti-inflammatory properties of microglia (P2X4R, CX3CR1, TREM2). BTK: Bruton’s tyrosine kinase, CSF-1R: colony-stimulating factor 1 receptor, CX3CR1: CX3 chemokine receptor 1, IFNγ: Interferon-γ, IL: interleukin, NO: nitric oxide, P2X4R: purinergic receptor P2X4, ROS: reactive oxygen species, S1PR: sphingosine-1-phosphate receptor, TGF: transforming growth factor, TNF: tumor necrosis factor, TREM2: triggering receptor expressed on myeloid cells.