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Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis

Grant number: 16/05377-3
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): July 01, 2016
Effective date (End): September 30, 2020
Field of knowledge:Biological Sciences - Pharmacology
Principal Investigator:José Carlos Farias Alves Filho
Grantee:Douglas da Silva Prado
Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID
Associated scholarship(s):18/25690-3 - Role of the ERK5-dependent signaling pathway in the differentiation of Th17 and Treg cells and in the development of experimental autoimmune encephalomyelitis, BE.EP.DR


T regulatory (Tregs) and T helper 17 (Th17) cells have distinct roles on autoimmune diseases development. Tregs are responsible for controlling homeostasis and immune tolerance, while Th17 cells are self-reactive lymphocytes that orchestrate tissue injury. Thereby, modulation on Treg and Th17 cells is a critical target on new therapeutic approaches development. ERK5 (Extracellular-signal-regulated kinase 5), an atypical member from mitogen-activated protein kinases (MAPK) proteins family, modulate many cellular process, as cellular proliferation, differentiation and survival. One of its unusual features is that in addition to the kinase function, it also acts as scaffold protein, transcription factor or cofactor. Furthermore, it is important on SMRT inhibition, which is a corepressor of PPAR³ receptor that modulates T cell fate destiny to Treg or Th17. Importantly, TGF-², activate ERK5 in kidney epithelial cells, suggesting another evidence of ERK5 role on T cell differentiation. Moreover, it was shown that TGF-² could induce ERK5 phosphorylation in epithelial cells, suggesting another role of this MAPK on T cell differentiation. Nevertheless, there are few data about its role on immune system cells and without data on T cell differentiation and autoimmune diseases development. Thereby, our hypothesis is that ERK5 is activated by TGF-², with consequent activation of PPAR-³ and modulation on Treg/Th17 cell differentiation. Our previous results shown that ERK5 upregultes Treg differentiation and downregulates Th17. Therefore, ERK5 could mediate autoimmune diseases development by Treg/Th17 balance, with great potential to be a new pharmacological target in the development of new therapeutic approaches.

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Scientific publications (4)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PRADO, DOUGLAS SILVA; VERAS, FLAVIO P.; FERREIRA, RAPHAEL GOMES; DAMASCENO, LUIS EDUARDO ALVES; MELO, PAULO HENRIQUE; ZAMBONI, DARIO SIMOES; CUNHA, THIAGO MATTAR; CUNHA, FERNANDO QUEIROZ; ALVES-FILHO, JOSE CARLOS. NLRP12 controls arthritis severity by acting as a checkpoint inhibitor of Th17 cell differentiation. FASEB JOURNAL, v. 34, n. 8, . (13/08216-2, 16/05377-3)
ALVES DAMASCENO, LUIS EDUARDO; PRADO, DOUGLAS SILVA; VERAS, FLAVIO PROTASIO; FONSECA, MIRIAM M.; TOLLER-KAWAHISA, JULIANA E.; ROSA, MARCOS HENRIQUE; PUBLIO, GABRIEL AZEVEDO; MARTINS, TIMNA VARELA; RAMALHO, FERNANDO S.; WAISMAN, ARI; et al. PKM2 promotes Th17 cell differentiation and autoimmune inflammation by fine-tuning STAT3 activation. JOURNAL OF EXPERIMENTAL MEDICINE, v. 217, n. 10, . (13/08216-2, 16/05377-3, 17/01714-8, 18/23910-6, 16/10280-9)
LUIZ, JOAO PAULO M.; TOLLER-KAWAHISA, JULIANA E.; VIACAVA, PAULA R.; NASCIMENTO, DANIELE C.; PEREIRA, PRISCILLA T.; SARAIVA, ANDRE L.; PRADO, DOUGLAS S.; LEBERT, MARC; GIURISATO, EMANUELE; TOURNIER, CATHY; et al. MEK5/ERK5 signaling mediates IL-4-induced M2 macrophage differentiation through regulation of c-Myc expression. Journal of Leukocyte Biology, . (17/20692-5, 13/08216-2, 11/12671-1, 17/01714-8, 16/05377-3)
PRADO, D. S.; DAMASCENO, L. E. A.; SONEGO, A. B.; ROSA, M. H.; MARTINS, T. V.; FONSECA, M. D. M.; CUNHA, T. M.; CUNHA, F. Q.; ALVES-FILHO, J. C.. Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism. International Immunopharmacology, v. 91, . (16/05377-3, 13/08216-2)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PRADO, Douglas da Silva. Role of the ERK5-dependent signaling pathway in the differentiation of Th17 and Treg cells and in the development of experimental autoimmune encephalomyelitis. 2020. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.

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