Central nervous system macrophages in progressive multiple sclerosis: relationship to neurodegeneration and therapeutics

Abstract

There are over 15 disease-modifying drugs that have been approved over the last 20 years for the treatment of relapsing-remitting multiple sclerosis (MS), but there are limited treatment options available for progressive MS. The development of new drugs for the treatment of progressive MS remains challenging as the pathophysiology of progressive MS is poorly understood.The progressive phase of MS is dominated by neurodegeneration and a heightened innate immune response with trapped immune cells behind a closed blood-brain barrier in the central nervous system. Here we review microglia and border-associated macrophages, which include perivascular, meningeal, and choroid plexus macrophages, during the progressive phase of MS. These cells are vital and are largely the basis to define lesion types in MS. We will review the evidence that reactive microglia and macrophages upregulate pro-inflammatory genes and downregulate homeostatic genes, that may promote neurodegeneration in progressive MS. We will also review the factors that regulate microglia and macrophage function during progressive MS, as well as potential toxic functions of these cells. Disease-modifying drugs that solely target microglia and macrophage in progressive MS are lacking. The recent treatment successes for progressive MS include include B-cell depletion therapies and sphingosine-1-phosphate receptor modulators. We will describe several therapies being evaluated as a potential treatment option for progressive MS, such as immunomodulatory therapies that can target myeloid cells or as a potential neuroprotective agent.

Keywords: Macrophages; Microglia; Multiple sclerosis; Neurodegeneration; Primary progressive; Secondary progressive; Therapeutics.

Fig. 1

Summary of microglia and macrophages in different types of MS lesions. A Lesions are colored where a lighter grey indicates decreased myelin density. Reactive microglia and macrophages are depicted with large cell bodies and are categorized where red indicates decreased, and orange indicates increased expression of what are typically considered homeostatic markers such as P2RY12 or CD163. Reactive microglia and macrophages are also categorized based on whether they contain lipid-rich myelin degradation products. Non-reactivated microglia and macrophages are depicted with small cell bodies and a ramified morphology. B Patterns of microglia and macrophage characteristics (density, ramification, and homeostatic marker expression) over time in different MS lesion types. EA (D) early active (demyelinating), LA (D) late active (demyelinating), MAI (D) mixed active–inactive (demyelinating), MAI (PD) mixed active–inactive (post-demyelinating), I inactive. For A and B, active (post-demyelinating) lesions are not depicted due to limited histopathological assessments of microglia and macrophage characteristics

Fig. 2

Extracellular factors regulating microglia and macrophage reactivity in progressive MS. Many characteristic features of MS pathophysiology may lead to the microglia and macrophages reactivity. Accumulation of meningeal inflammation, including accumulation of B cells, T cells and macrophages, results in microglia and macrophages reactivity in the underlying cortex. Leakage of the BBB results in blood components such as fibrinogen leaking into the CNS. Once in the CNS, fibrinogen is converted to fibrin which acts as a potent stimulus of microglia and macrophages. Demyelination and death of iron-rich oligodendrocytes release excess iron into the extracellular space, which can in turn act as a stimulus for microglia and macrophages

Fig. 3

Microglia and macrophage mediated mechanisms of neurodegeneration in progressive MS. Microglia and macrophages release many cytokines, including TNF-a, and IL-1β, which may contribute to neurodegeneration via cytokine induced cell death, inhibition of astrocytic glutamate reuptake, and via the induction of dysfunctional RNA binding proteins. Microglia and macrophages can also release glutamate, potentially contributing to glutamate excitotoxicity and neurodegeneration. Lastly, microglia and macrophages release ROS/RNS which may contribute to neurodegeneration by inducing oxidative stress and mitochondrial injury

Fig. 4

Phase 2/3 clinical trial of drugs and DMDs approved for progressive MS. The registration numbers with clinicaltrials.gov are shown in brackets for drugs currently being assessed in phase 2/3 clinical trials as potential treatments for progressive MS. The references for the published findings are also indicated in brackets (if applicable)