Animal Models of MS Reveal Multiple Roles of Microglia in Disease Pathogenesis

Abstract

Multiple sclerosis (MS) is a progressive inflammatory and demyelinating disease that affects more than 2.5 million people worldwide every year. Current therapies use mostly disease-modifying drugs, focusing on blocking and regulating systemic functions and the central nervous system (CNS) infiltration of immune cells; however, these therapies only attenuate or delay MS symptoms, but are not effective in halting the disease progression. More recent evidence indicated that regulation of inflammation within the CNS might be a better way to approach the treatment of the disease and microglia, the resident immune cells, may be a promising target of therapeutic studies. Microglia activation classically accompanies MS development, and regulation of microglia function changes the outcome of the disease. In this paper, we review the contributions of microglia to MS pathogenesis and discuss microglial functions in antigen presentation, cytokine release, and phagocytosis. We describe data both from animal and human studies. The significant impact of the timing, intensity, and differentiation fate of activated microglia is discussed, as they can modulate MS outcomes and potentially be critically modified for future therapeutic studies.

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

“…The aggravation of the clinical symptoms of EAE started about 1 wk after the peak of the second episode. This finding could be attributed to the new notion that the activation of resident microglia contributes to both detrimental and protective aspects of the inflammatory process (4,38). Thus, depending on the timing, brain microglia participates in inflammation (as in the first EAE episode), does not participate in inflammation (as in the second EAE episode), or participates again (as in the third EAE episode).…”

“…Consequently, experimental autoimmune encephalomyelitis (EAE), an animal model of MS, provides a powerful tool for investigating the pathogenesis of MS. Immunization of several rodent strains with various neuroantigens has resulted in the induction of different types of EAE (2)(3)(4) that correspond to different phases of the human disease (5). Because of the variable inflammation, demyelination, remyelination, glial proliferation, and neurodegeneration in the CNS white matter and gray matter, information (obtained noninvasively) about the early symptoms and diagnosis of MS, disease progression, and responses to various treatments would be beneficial for MS management.…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…Until recently, no clearly defined lesion stage-dependent phenotype was identified. Macrophages and microglia were considered to present an intermediate phenotype in human MS lesions (Vogel et al 2013;Peferoen et al 2015) with a predominance of proinflammatory phenotypes during the acute or early phase of disease (Gao and Tsirka 2011). Microglia in human CNS tissue express a pattern of G-protein-coupled sphingosine-1-phosphate (S1P) receptors similar to mature dendritic cells (DCs) and macrophages but distinct from that seen in circulating monocytes (Hunter et al 2016).…”

“…A classically activated, M1-like state (associated with host defense, cytotoxicity, secretion of proinflammatory cytokines, proteases, and ROS and reactive nitrogen [RNI] species) defines proinflammatory, activated microglia that are involved in the development and expansion of lesions (Gao and Tsirka 2011). Activated microglia present cell-surface-expressed molecules such as CD14 and MHC, which allow T cells to recognize and bind to small fragments of pathogens (Block and Hong 2007).…”

“…Once activated APCs are recruited, they present myelin antigens associated with MHC class II and express costimulatory molecules (e.g., CD40 and B7 glycoproteins) capable of further activating infiltrating T cells (Sanders and De Keyser 2007). Microglia also regulate T-cell differentiation toward T helper (Th)1 and Th17 pathogenic subtypes through TNF-α (Gao and Tsirka 2011).…”