ISSN 0006-2979, Biochemistry (Moscow), 2018, Vol. 83, No. 9, pp. 1089-1103. © Pleiades Publishing, Ltd., 2018. Original Russian Text © V. S. Gogoleva, K.-S. N. Atretkhany, M. S. Drutskaya, I. A. Mufazalov, A. A. Kruglov, S. A. Nedospasov, 2018, published in Biokhimiya, 2018, Vol. 83, No. 9, pp. 1368-1384. REVIEW Cytokines as Mediators of Neuroinflammation in Experimental Autoimmune Encephalomyelitis V. S. Gogoleva1,2,a*, K.-S. N. Atretkhany1,2, M. S. Drutskaya1,2, I. A. Mufazalov3, A. A. Kruglov4, and S. A. Nedospasov1,2,4,b* 1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia 2Lomonosov Moscow State University, Biological Faculty, 119234 Moscow, Russia 3University of California, San Francisco, CA 94143, USA 4Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119234 Moscow, Russia ae-mail: [email protected] be-mail: [email protected] Received May 12, 2018 Revision received June 10, 2018 Abstract—Cytokines play a pivotal role in maintaining homeostasis of the immune system and in regulation of the immune response. Cytokine dysregulation is often associated with development of various pathological conditions, including autoimmunity. Recent studies have provided insights into the cytokine signaling pathways that are involved not only in pathogenesis of autoimmune neuroinflammatory disorders, such as multiple sclerosis, but also in neurodegenerative states, for example, Alzheimer’s disease. Understanding the exact molecular mechanisms of disease pathogenesis and evaluation of relevant experimental animal models are necessary for development of effective therapeutic approaches. DOI: 10.1134/S0006297918090110 Keywords: experimental autoimmune encephalomyelitis, inflammation, neurodegeneration, proinflammatory cytokines, TNF, IL-6, IL-17A In developed countries, aging of the population is a blood and soluble factors produced by them. This barrier risk factor for development of central nervous system is maintained by tight junctions between the brain (CNS) disorders. Despite the steadily increasing number endothelial cells, their basal membrane, pericytes and of patients with these serious diseases, up to now no effec- astrocytes. However, recent studies in neuroimmunology tive therapy for such neuropathologies has been devel- have shown that an interaction of the immune system oped. For a long time, it was believed that the CNS does components with the CNS is required for maintaining not interact with the immune system because of its homeostasis and that homeostatic imbalance caused by immune privilege being maintained, in particular, by the inflammatory processes may lead to various pathologies. blood-brain barrier (BBB). The BBB is a physical border Thus, immune dysregulation and development of patho- between the CNS and immune cells circulating in the logical processes trigger the effector immune response to CNS-specific antigens that is mediated by infiltration of Abbreviations: AD, Alzheimer’s disease; BBB, blood-brain bar- the circulating immune cells into the CNS and by activa- rier; CCR, chemokine receptor; CNS, central nervous system; tion of the CNS-resident cells. In the inflammatory EAE, experimental autoimmune encephalomyelitis; GM-CSF, microenvironment the infiltrating and resident cells of granulocyte-macrophage colony-stimulating factor; gp130, the CNS secrete cytokines which in steady state regulate glycoprotein 130; IFN, interferon; IL, interleukin; IL-1R1, IL- the immune response and homeostasis. Proinflammatory 1β receptor subunit; IL-6R, interleukin-6 receptor; LT, lym- cytokines play a pivotal role in the pathogenesis of photoxin; MOG, myelin oligodendrocyte protein; MS, multi- autoimmune diseases, in particular, of those associated ple sclerosis; NK-cells, natural killer cells; TGFβ, transforming growth factor beta; Th, T helper; TNF, tumor necrosis factor; with pathology of the nervous system. For instance, TNFR, tumor necrosis factor receptor; Tregs, regulatory T increased levels of many proinflammatory cytokines, cells. such as interleukins 6, 1, 17 (IL-6, IL-1, IL-17) and * To whom correspondence should be addressed. tumor necrosis factor (TNF), were found in the cere- 1089 1090 GOGOLEVA et al. brospinal fluid and in demyelinating plaques of patients associated with the accumulation of misfolded proteins in with multiple sclerosis (MS) suggesting their possible the brain causing neuronal damage in different brain involvement in the pathogenesis of MS [1, 2]. The roles of regions [3, 4]. The role of the immune system in the various cytokines in neuroinflammation and neurodegen- pathogenesis of these diseases is intensively studied, par- eration have been investigated in the mouse experimental ticularly, in mouse models. Thus, systemic inflammation models using reverse genetics approach. in mice may promote the accumulation of a β-amyloid precursor that further results in development of patholog- ical processes specific for AD: the accumulation of β- NEURODEGENERATIVE DISEASES amyloid plaques and activation of microglia [5]. Genetic AND NEUROINFLAMMATION studies have revealed the association between predisposi- tion to AD and mutations in the gene encoding the trig- Alzheimer’s disease (AD), Parkinson’s disease (PD) gering receptor expressed on myeloid cells 2 (TREM2) and amyotrophic lateral sclerosis (ALS) are the most fre- which is present on the microglia cell surface [6, 7]. It has quent and best studied neurodegenerative diseases. It is been shown that in a mouse model of AD microglia thought that initiation of neurodegenerative diseases is acquires a protective phenotype in a two-step process due Role of cytokines in the development of neuroinflammatory and neurodegenerative diseases. During the neuroinflammation, priming occurs in peripheral lymphoid organs with subsequent differentiation of effector T cells due to cytokines being released by antigen-presenting cells (1). Then the increased BBB permeability promotes the infiltration of lymphoid and myeloid cells into the CNS (2, 3). The infiltrating cells recruit other immune cells from the periphery through the production of cytokines and also activate CNS-resident cells driving inflammation in the CNS. The development of neurodegenerative diseases is characterized by accumulation of protein aggregates (I). This process results in the activation of stromal cells and phagocytes of the CNS, i.e., astrocytes and microglia, respectively (II). Subsequently, astrocytes and microglia secrete cytokines, and this chronic CNS-intrinsic cytokine production is associated with loss of tissue function. The effector phase of neuroinflammatory and neurodegenerative diseases is characterized by neuronal damage and local inflammation in the CNS. (Materials of the Servier Medical Art were used for the figure) BIOCHEMISTRY (Moscow) Vol. 83 No. 9 2018 CYTOKINES IN NEUROINFLAMMATION 1091 to increased expression of genes responsible for phagocy- protein (MBP), myelin oligodendrocyte protein (MOG) tosis of the accumulated β-amyloid plaques [8]. Another or proteolipid protein (PLP) are used as antigens for the study found that the microglia phenotype depends on disease induction. Moreover, a model of spontaneous activation of TREM2–APOE signaling pathway which is EAE development was established using transgenic mice associated with the pathogenic role of the microglia in the with overexpression of the antigen-specific T- or B-cell neurodegeneration model [9]. Recent data have identi- receptor [19]. However, it should be noted that EAE is not fied that the inflammation, mainly initiated by activated an ideal model of multiple sclerosis. First, mice on myeloid cells, plays an important role in the pathogenesis C57BL/6 background, a commonly used mouse strain in of AD. Thus, the immune system is believed to play an immunological studies, show a monophasic disease important role in the pathogenesis of this neurodegener- course, whereas the most frequent MS type is relapsing- ative disorder [10]. remitting MS characterized by periods of exacerbation Mechanisms of development and pathogenesis of and recovery. Second, the composition of key cell popu- neurodegenerative and neuroinflammatory diseases are lations involved in the adaptive arm of immune response different. First, the main causes of neurodegenerative dis- during EAE can vary, depending on the chosen antigen or eases are protein aggregates of β-amyloid, α-synuclein on the mouse strain. Thus, when the disease is induced and a mutant form of superoxide dismutase 1 (SOD1) in with the MOG35-55-peptide, the T cell response in the case of AD, PD, and the hereditary form of ALS, C57BL/6 mice is characterized mainly by CD4+ T cells, respectively [11]. On the other hand, in the classical neu- whereas in humans CD8+ T cells and B cells are also roinflammatory disease, i.e., multiple sclerosis, patholog- involved [20, 21]. In clinical studies, the efficiency of B- ical processes are mainly mediated by cells of the immune cell depletion has been already approved, whereas the role system. Second, in proteinopathies, proinflammatory of B cells in EAE requires further investigation. It has cytokines are mainly produced by myeloid cells, predom- been demonstrated that B cells can modulate the severity inantly, CNS-resident cells, whereas in neuroinflamma- of the disease by their antigen-presenting function, as tion cytokines are produced by both T cells and myeloid well as via secretion of anti-inflammatory cytokines IL- cells [12, 13].