Involvement of Indoleamine-2,3-Dioxygenase and Kynurenine Pathway in Experimental Autoimmune Encephalomyelitis in Mice
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ORIGINAL PAPER
Involvement of Indoleamine‑2,3‑Dioxygenase and Kynurenine Pathway in Experimental Autoimmune Encephalomyelitis in Mice Micheli Stéfani Zarzecki1 · Leandro Cattelan Souza1 · Renata Giacomeli1 · Marcia Rósula Poetini Silva1 · Marina Prigol1 · Silvana Peterini Boeira1 · Cristiano Ricardo Jesse1 Received: 27 June 2020 / Revised: 21 September 2020 / Accepted: 5 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The experimental autoimmune encephalomyelitis (EAE) is a model that mimics multiple sclerosis in rodents. Evidence has suggested that the activation of indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme in the kynurenine pathway (KP), plays a crucial role in inflammation-related diseases. The present study aimed to investigate the involvement of the inflammatory process and KP components in a model of EAE in mice. To identify the role of KP in EAE pathogenesis, mice received IDO inhibitor (INCB024360) at a dose of 200 mg/kg (per oral) for 25 days. We demonstrated that IDO inhibitor mitigated the clinical signs of EAE, in parallel with the reduction of cytokine levels (brain, spinal cord, spleen and lymph node) and ionized calcium-binding adaptor protein-1 (Iba-1) gene expression in the central nervous system of EAE mice. Besides, IDO inhibitor causes a significant decrease in the levels of tryptophan, kynurenine and neurotoxic metabolites of KP, such as 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) in the prefrontal cortex, hippocampus, spinal cord, spleen and lymph node of EAE mice. The mRNA expression and enzyme activity of IDO and kynurenine 3-monooxygenase (KMO) were also reduced by IDO inhibitor. These findings indicate that the inflammatory process concomitant with the activation of IDO/KP is involved in the pathogenic mechanisms of EAE. The modulation of KP is a promising target for novel pharmacological treatment of MS. Keywords Autoimmune disease · Central nervous system · Glial activation · Inflammation · Tryptophan metabolism · Multiple sclerosis
Introduction Multiple sclerosis (MS) is an inflammatory neurodegenerative disease characterized by neuronal demyelination in the central nervous system (CNS), which is related to an autoimmune response against components of myelin [1]. MS is marked by neurological disability, including sensorial, motor, autonomic and neurocognitive deficits. Affecting around 2.5 million individuals worldwide, the prevalence and incidence of MS are higher for women than men (ranging female to male ratio of 2:1) [2]. Although genetic and environmental factors are implicated in the pathogenesis of MS, the molecular mechanisms * Leandro Cattelan Souza [email protected] 1
Laboratory of Pharmacological and Toxicological Evaluations Applied to Bioactive Molecules, Federal University of Pampa, Itaqui, RS CEP 97650‑000, Brazil
underlying the pathophysiology of this disease is not fully elucidated. It is believed that autoreactive T cell responses have a crucial role in the pathogenesis of MS [1
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