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Review
. 2019 Mar 22:10:286.
doi: 10.3389/fphar.2019.00286. eCollection 2019.

Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis

Jiaying Wang  1 , Jiajia Wang  1 , Jincheng Wang  1 , Bo Yang  1 , Qinjie Weng  1   2 , Qiaojun He  1   2
Affiliations
Review

Targeting Microglia and Macrophages: A Potential Treatment Strategy for Multiple Sclerosis

Jiaying Wang et al. Front Pharmacol. .

Abstract

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system (CNS). The early stage is characterized by relapses and the later stage, by progressive disability. Results from experimental and clinical investigations have demonstrated that microglia and macrophages play a key part in the disease course. These cells actively initiate immune infiltration and the demyelination cascade during the early phase of the disease; however, they promote remyelination and alleviate disease in later stages. This review aims to provide a comprehensive overview of the existing knowledge regarding the neuromodulatory function of macrophages and microglia in the healthy and injured CNS, and it discusses the feasibility of harnessing microglia and macrophage physiology to treat MS. The review encourages further investigations into macrophage-targeted therapy, as well as macrophage-based drug delivery, for realizing efficient treatment strategies for MS.

Keywords: central nervous system; macrophages; microglia; multiple sclerosis; targeted therapy.

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Figures

FIGURE 1
FIGURE 1
Origin of tissue macrophages in healthy CNS. Microglia and tissue-resident macrophages are derived from prenatal sources. The primitive erythromyeloid precursors (EMPs) located in the yolk sac during E7.5∼8.0 soon develop into A1 cells and finally become A2 cells. The matured A2 cells then differentiate into microglia, meningeal macrophages (mMø), perivascular macrophages (pvMø), and choroid-plexus macrophages (cpMø). However, after birth, cpMΦ originate exclusively from bone Ly6chi monocytes.
FIGURE 2
FIGURE 2
Proposed actions of disease-modifying multiple sclerosis therapies targeting macrophages. In the periphery, bryostatin-1 promotes the differentiation of lymphocytes into anti-inflammatory Th2 cells by acting on macrophages. Ethyl pyruvate prevents the activation of macrophages/microglia within the CNS. Lenalidomide, spermidine, forskolin, and the novel PADRE-Kv1.3 vaccine can promote macrophage/microglia M2 polarization. Transplanting GAS5-downregulated microglia into the lateral ventricles of EAE mice could promote remyelination. Exogenous supplementation of M2 macrophages such as PD-L1+/PD-L2+ M2 cells can also alleviate demyelination. Micro-based drug delivery systems for delivering GC to targeted macrophages have been widely used in EAE. As macrophages can easily migrate into the brain during MS, they can be used as cellular vehicles for the delivery of small drugs, RNAs, and proteins to the brain parenchyma. Macrophage exosomes could cross the BBB and deliver BDNF to recover injury. HMGB1, high-mobility group box 1; GC, glucocorticoids; MR, mineralocorticoid receptors; CLRs, C-type lectin receptors.
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