Manipulating Macrophage/Microglia Polarization to Treat Glioblastoma or Multiple Sclerosis

Abstract

Macrophages and microglia are implicated in several diseases with divergent roles in physiopathology. This discrepancy can be explained by their capacity to endorse different polarization states. Theoretical extremes of these states are called M1 and M2. M1 are pro-inflammatory, microbicidal, and cytotoxic whereas M2 are anti-inflammatory, immunoregulatory cells in favor of tumor progression. In pathological states, these polarizations are dysregulated, thus restoring phenotypes could be an interesting treatment approach against diseases. In this review, we will focus on compounds targeting macrophages and microglia polarization in two very distinctive pathologies: multiple sclerosis and glioblastoma. Multiple sclerosis is an inflammatory disease characterized by demyelination and axon degradation. In this case, macrophages and microglia endorse a M1-like phenotype inducing inflammation. Promoting the opposite M2-like polarization could be an interesting treatment strategy. Glioblastoma is a brain tumor in which macrophages and microglia facilitate tumor progression, spreading, and angiogenesis. They are part of the tumor associated macrophages displaying an anti-inflammatory phenotype, thereby inhibiting anti-tumoral immunity. Re-activating them could be a method to limit and reduce tumor progression. These two pathologies will be used to exemplify that targeting the polarization of macrophages and microglia is a promising approach with a broad spectrum of applications deserving more attention.

Keywords: glioblastoma; macrophage; microglia; multiple sclerosis; polarization; therapeutic; treatments.

Figure 1

Different populations and origins of macrophages. Two major populations of macrophages coexist in the body: the macrophages that reside and self-renew in the tissues and the ones differentiated from the monocytes circulating in the blood and originating from the hematopoietic stem cells. Most tissue resident macrophages have an embryonic origin and arise either from the yolk sac (for example microglia in the brain) or directly from the fetal liver (for example, Kupffer cells in the liver and kidney macrophages). Some tissue resident macrophages are peripherally derived such as intestinal macrophages. All these tissue resident macrophages constitute a heterogeneous population with tissue-specific functions.

Figure 2

Macrophage polarization states. In the tissues, macrophages can adopt several polarization types corresponding to different activation states. The theoretical extremes of these states are, on one hand, the M1-like macrophages with pro-inflammatory effects, and on the other hand, the M2-like macrophages with anti-inflammatory effects. M1-like macrophages can be obtained by stimulation with interferon-γ, secreted by other M1-like macrophages, Th1 lymphocytes, and NK cells; GM-CSF secreted by M1-like macrophages and parenchymal cells or LPS present on Gram-negative bacteria. M2a alternatively activated macrophages were obtained by stimulation with IL-4 and IL-13 secreted by mast cells, basophils, and Th2 lymphocytes. M2b type II macrophages were obtained after stimulation with immune complexes or LPS. Finally, M2c deactivated macrophages were obtained by stimulation with IL-10 secreted by mast cells, M2-like macrophages, and Th2 lymphocytes or after treatment with glucocorticoids such as dexamethasone. GM-CSF: granulocyte-macrophage colony-stimulating factor, IL: interleukin, LPS: lipopolysaccharide, Th: T helper.

Figure 3

Macrophages have opposing effects in two pathologies of the central nervous system: multiple sclerosis and glioblastoma. In multiple sclerosis (A), macrophages exert a M1-like phenotype and thereby attack and destroy the myelin sheath and damage the axons in the CNS. In glioblastoma (B), these cells adopt the opposite M2-like phenotype favoring an anti-inflammatory milieu. Consequently, tumorigenesis, tumor-spreading, and angiogenesis is promoted whereas cytotoxic T-cells are inhibited. CNS: central nervous system, TAMs: tumor associated macrophages.

Figure 4

Targeting macrophage polarization in multiple sclerosis. In MS, macrophages adopt a M1-like phenotype promoting inflammation. A strategy for the resolution of inflammation and myelin sheath destruction is to target this polarization and push the macrophages toward a M2-like anti-inflammatory phenotype. Several compounds on the market and in development use different methods to re-educate macrophages. One strategy is to promote the secretion of anti-inflammatory cytokines by macrophages and Th2/Treg lymphocytes (A). Another strategy is to promote the activation of Th2 and Treg lymphocytes (B). Another way to achieve this purpose is to inhibit the secretion of pro-inflammatory cytokines by macrophages and Th1 lymphocytes (C). Preventing antigen presentation by macrophages is another strategy (D). A last strategy is to limit extravasation of monocytes into the CNS (E). APC: antigen presenting cell, MS: multiple sclerosis, Th: T helper, Treg: regulatory T cells.

Figure 5

Targeting macrophage polarization in glioblastoma. In GBM, macrophages adopt a M2-like phenotype inhibiting inflammation and anti-tumoral immunity. A strategy for the reactivation of this immunity is to target the polarization of macrophages in order to promote M1 activation. A first strategy is to inhibit targets promoting M2 polarization such as CSF1R and STAT3 or the recognition of CD47 by SIRPα (A). Another strategy is to activate targets favoring M1 polarization such as TLR9 and CD40 (B). A last strategy is to inhibit the attraction of M2 polarized TAMs from the circulation toward the CNS (C). CSF1R: colony-stimulating factor 1 receptor, SIRPα: signal regulatory protein α, TAMs: tumor associated macrophages, TLR: Toll-like receptor.