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Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis

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dc.contributor.author Correale, Jorge
dc.date.accessioned 2021-02-22T14:33:54Z
dc.date.available 2021-02-22T14:33:54Z
dc.date.issued 2021-01-20
dc.identifier.citation Correale J. Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis. Front Immunol. 2021 Jan 20;11:600428. doi: 10.3389/fimmu.2020.600428 en_US
dc.identifier.uri https://doi.org/10.3389/fimmu.2020.600428
dc.identifier.uri https://repositorio.fleni.org.ar/handle/123456789/364
dc.description.abstract Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. Although the pathogenesis of MS is not yet fully elucidated, several evidences suggest that autoimmune processes mediated by Th1, Th17, and B cells play an important role in the development of the disease. Similar to other cells, immune cells need continuous access to amino acids (AA) in order to maintain basal metabolism and maintain vitality. When immune cells are activated by inflammation or antigenic signals, their demand for AA increases rapidly. Although AA deprivation itself may weaken the immune response under certain conditions, cells also have AA sensitive pathways that can activate intense alterations in cell metabolism based on changes in AA levels. Several data indicate that cells expressing enzymes that can degrade AA can regulate the functions of antigen-presenting cells and lymphocytes, revealing that the AA pathways are essential for controlling the function, and survival of immune cells, as well as immune cell gene expression. Basal AA catabolism may contribute to immune homeostasis and prevent autoimmunity, while increased AA catalytic activity may enhance immune suppression. In addition, there is increasing evidence that some downstream AA metabolites are important biological mediators of autoimmune response regulation. Two of the most important AA that modulate the immune response are L-Tryptophan (Trp) and L-Arginine (Arg). Tryptophan is catabolized through 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 enzymes, while three other enzymes catabolize Arg: inducible nitric oxide synthetase (iNOS), and two arginase isoforms (ARG1, ARG2). Genes encoding IDO, iNOS and ARG are induced by inflammatory cues such as cytokines, a key feature that distinguishes them from enzymes that catabolize other AA. Evidence suggests that AA catabolism is decreased in MS patients and that this decrease has functional consequences, increasing pro-inflammatory cytokines and decreasing Treg cell numbers. These effects are mediated by at least two distinct pathways involving serine/threonine kinases: the general control nonderepressible 2 kinase (GCN2K) pathway; and the mammalian target of rapamycin (mTOR) pathway. Similarly, IDO1-deficient mice showed exacerbation of experimental autoimmune encephalomyelitis (EAE), increased Th1 and Th17 cells, and decreased Treg cells. On the contrary, the administration of downstream Trp metabolite 3-HAA, inhibits Th1/Th17 effector cells and promotes Treg response by up-regulating TGF-β production by dendritic cells, thereby improving EAE. Collectively, these observations stand out the significance of AA catabolism in the regulation of the immune responses in MS patients. The molecules related to these pathways deserve further exploration as potential new therapeutic targets in MS en_US
dc.language.iso eng en_US
dc.publisher Frontiers Research Foundation en_US
dc.rights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/2.5/ar/
dc.subject Multiple Sclerosis en_US
dc.subject Esclerosis Múltiple en_US
dc.subject Amino Acids en_US
dc.subject Aminoácidos en_US
dc.subject Tryptophan en_US
dc.subject Triptofanasa en_US
dc.subject Arginine en_US
dc.subject Arginina en_US
dc.subject Rapamycin en_US
dc.subject Rapamicina en_US
dc.subject Kynurenine en_US
dc.subject Quinurenina en_US
dc.title Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis en_US
dc.type info:eu-repo/semantics/publishedVersion
dc.type info:eu-repo/semantics/article en_US
dc.description.fil Fil: Correale, Jorge. Fleni. Departamento de Neurología. Servicio de Neuroinmunología y Enfermedades Desmielinizantes; Argentina.
dc.relation.ispartofCOUNTRY Suiza
dc.relation.ispartofCITY Lausana
dc.relation.ispartofTITLE Frontiers in immunology
dc.relation.ispartofISSN 1664-3224
dc.type.snrd info:ar-repo/semantics/artículo es_ES


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