Macrophages in Multiple Sclerosis (MS)

Multiple sclerosis (MS) is an inflammatory and chronic neurodegenerative disease, causing neurological disability among young adults. The presence of lesions as a result of inflammation as well as axonal loss, primary demyelination, reactive gliosis in the central nervous system (CNS) are the pathological features of MS. These features may occur at the same time and are often thought to correlate with whole and diffuse changes of the CNS. Clinically, the presentation of MS varies and depends on the areas affected by the disease. Peripheral inflammatory cells are known to infiltrate into the CNS tissues, possibly resulting from the breakdown of the blood-brain barrier in the diseased state. The infiltrating peripheral inflammatory cells are predominantly macrophages and microglia.

Polarization of Macrophages in MS

Macrophage polarization is tuned by a network of signaling molecules, transcription factors, epigenetic mechanisms, and post-transcriptional regulators. M1 phenotype of macrophages can produce proinflammatory cytokines, chemokines, and nitric oxide (NO). Moreover, they show an increased ability to present antigens, cause phagocytic infections induced by bacterial, viral, or fungal factors, as well as kill tumor cells. Unlike M1 macrophages, M2 macrophages do not display any cytotoxic properties, they contribute to parasite clearance, and, in allergic reactions, they have functions related to tissue remodeling, angiogenesis promotion, tumor progression, and immunoregulation. M2-polarized macrophages are further subdivided into M2a, M2b, and M2c. Macrophages are multifunctional cells that do not stay in a constantly active state. In addition, they are often in the process of dynamically changing from M1 to M2, or the reverse, depending on the environment in which they live.

Functions of Macrophages in MS

Reactive macrophages can mediate cell injury or neuroprotective effects in MS, and they promote the relapsing-remitting feature of MS. During the acute phase, macrophages become the M1 macrophages immediately after activation, and they potentially release a large number of proinflammatory cytokines, which are thought to induce tissue damage, demyelination, and neuronal death in the CNS. The M2 macrophages undergo a gradual increase during the process of inflammation until the peak of disease, whereas the amount of M1 macrophages is decreased. During the later phase, M2 macrophages are predominant in the CNS, where they can release a variety of anti-inflammatory cytokines such as interleukin 13 (IL-13), IL-33, IL-4, IL-10, and transforming growth factorβ (TGFβ).

Fig.1 Roles of M1/M2 microglia and the effect of different drugs on these cells in MS.¹

Therapies of Targeting Macrophages

• Inhibiting the inflammatory effector functions and blockade of M1 macrophages recruitment: by a variety of compounds such as teriflunomide, interferon β (IFN-β), glatiramer acetate, resveratrol, neuropeptide Y, valproic acid, tuftsin, and fasudil; by microRNAs; blocking antibodies for granulocyte-macrophage colony-stimulating factor (GM-CSF).
• Inhibiting the activation of macrophages: Ethyl pyruvate, IFN-β, glucocorticoids, glatiramer acetate, fingolimod.
• Augmentation and restoration of the anti-inflammatory phenotype M2 cells by Lenalidomide, spermidine, forskolin, estrogen.
• Depleting specific macrophages by Liposomes or nanoparticles.
• Macrophages can be used as cellular vehicles for the delivery of small drugs, RNAs, and proteins.
• Modulation of pro-remyelination via microglia. The retinoid X receptor (RXR) agonists hold promise to reverse deficiencies in phagocytosis and remyelination.

Fig.2 Proposed actions of disease-modifying MS therapies targeting macrophages. (Wang, 2019)

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References

1. Radandish, Maedeh, Parvin Khalilian, and Nafiseh Esmaeil. "The role of distinct subsets of macrophages in the pathogenesis of MS and the impact of different therapeutic agents on these populations." Frontiers in Immunology 12 (2021): 667705.
2. Wang, Jiaying, et al. "Targeting microglia and macrophages: a potential treatment strategy for multiple sclerosis." Frontiers in Pharmacology 10 (2019): 286.