Should mast cells be considered therapeutic targets in multiple sclerosis?

Abstract

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

Keywords: central nervous system; degenerative disease; experimental autoimmune encephalomyelitis; immunity; immunomodulatory drugs; inflammatory disease; ketotifen fumarate; mast cells; multiple sclerosis; therapeutic target.

Figure 1

Morphological aspect of mast cells found in tissues (A) and in cell culture after in vitro differentiation (B). The presence of numerous granules that can be stained by several dyes, including toluidine blue (A) can be noticed. The granular aspect of mast cells can be also seen by using phase-contrast microscopy (B). Images obtained by Pinke, KH by using Axiostar Plus HBO 50/AC Zeiss conventional microscope or LEICA/DM IRBE inverted microscope, both located at Bauru School of Dentistry, University of São Paulo, Brazil.

Figure 2

MC contribution to MS/EAE development. MS and EAE are very complex autoimmune diseases involving different stages, many cell types, and a plethora of mediators. MCs are envisioned as pivotal players in the immunopathogenesis and thus as potential therapeutic targets in these pathologies. (A) Possible stages in which MCs could contribute to immunopathogenesis. (B) Some of the major immunological mechanisms by which these cells contribute to disease development in each of these main stages are illustrated. BBB: Blood-brain barrier; CNS: central nervous system; EAE: experimental autoimmune encephalomyelitis; IL-1β: interleukin 1 beta; MCs: mast cells; MMP: matrix metalloproteinase; MS: multiple sclerosis; PMN: polymorphonuclear leukocyte; TNF-α: tumor necrosis factor alpha.

Figure 3

Overview of the ketotifen effects on EAE immunopathogenesis. The graphical abstract illustrates the main findings reported by Pinke et al. (2019): a striking reduction of EAE prevalence observed after early administration of ketotifen fumarate (0.4 mg/kg) on EAE mice. The protective role of this mast cell stabilizer drug was associated with blood-CNS barrier normalization and the subsequent reduction of EAE pathological features on the CNS despite the presence of a typical encephalitogenic response in peripheral lymphoid organs. EAE: Experimental autoimmune encephalomyelitis; CNS: central nervous system; DCs: dendritic cells; IFN-γ: interferon γ; IL: interleukin.