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Title: GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice
Authors: Orsini, Heloisa [UNIFESP]
Araujo, Leandro Pires [UNIFESP]
Maricato, Juliana Terzi [UNIFESP]
Guereschi, Marcia Grando [UNIFESP]
Mariano, Mario [UNIFESP]
Castilho, Beatriz Amaral de [UNIFESP]
Basso, Alexandre S. [UNIFESP]
Universidade Federal de São Paulo (UNIFESP)
Keywords: EAE
Issue Date: 1-Mar-2014
Publisher: Elsevier B.V.
Citation: Brain Behavior and Immunity. San Diego: Academic Press Inc Elsevier Science, v. 37, p. 177-186, 2014.
Abstract: Experimental autoimmune encephalomyelitis (EAE) has been widely employed as a model to study multiple sclerosis (MS) and indeed has allowed some important advances in our comprehension of MS pathogenesis. Several pieces of evidence suggest that infiltrating Th1 and Th17 lymphocytes are important players leading to CNS demyelination and lesion during the peak of murine EAE. Subsequently, effector T cell responses rapidly decline and the recovery phase of the disease strongly correlates with the expression of anti-inflammatory cytokines and the enrichment of Foxp3+ regulatory T (Treg) cells within the target organ. However, the mechanisms leading to the increased presence of Treg cells and to the remission phase of the disease are still poorly understood. Recent researches demonstrated that chemically induced amino-acid starvation response might suppress CNS immune activity. Here we verified an important participation of the general control nonrepressible 2 (GCN2), a key regulator kinase of the amino-acid starvation response, in the development of the remission phase of EAE in C57BL/6 mice. By immunizing wild type C57BL/6 (WT) and GCN2 knock-out mice (GCN2 KO) with myelin oligodendrocyte glycoprotein peptide (MOG(35-55)), it was noticed that GCN2 KO mice did not develop the remission phase of the disease and this was associated with higher levels of CNS inflammation and increased presence of effector T cells (Th1/Th17). These animals also showed lower frequency of Treg cells within the CNS as compared to WT animals. Higher expression of indoleamine 2,3-dioxygenase (IDO) and higher frequency of plasmacytoid dendritic cells (pDCs) were found at the peak of the disease in the CNS of WT animals. Our results suggest that the GCN2 kinase-dependent sensing of IDO activity represents an important trigger to the EAE remission phase. the IDO-mediated immunoregulatory events may include the arresting of effector T cell responses and the differentiation/expansion of Treg cells within the target organ. (C) 2013 Elsevier Inc. All rights reserved.
ISSN: 0889-1591
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