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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

IL-33 signaling is essential to attenuate viral-induced encephalitis development by downregulating iNOS expression in the central nervous system

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Franca, Rafael F. O. [1] ; Costa, Renata S. [2] ; Silva, Jaqueline R. [2] ; Peres, Raphael S. [2] ; Mendonca, Leila R. [1] ; Colon, David F. [2] ; Alves-Filho, Jose Carlos [3] ; Cunha, Fernando Q. [3]
Número total de Autores: 8
Afiliação do(s) autor(es):
[1] Oswaldo Cruz Fdn FIOCRUZ, Dept Virol & Expt Therapy LAVITE, IAM, Av Prof Moraes Rego S-N, BR-50740465 Recife, PE - Brazil
[2] Univ Sao Paulo, Program Basic & Appl Immunol, BR-14049900 Ribeirao Preto, SP - Brazil
[3] Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Pharmacol, BR-14049900 Ribeirao Preto, SP - Brazil
Número total de Afiliações: 3
Tipo de documento: Artigo Científico
Citações Web of Science: 13

Background: Viral encephalitis is a common cause of lethal infections in humans, and several different viruses are documented to be responsible. Rocio virus is a flavivirus that causes a severe lethal encephalitis syndrome in humans and also mice, providing an interesting model to study the CNS compartmentalized immune response. Interleukin 33 (IL-33), a member of the IL-1 family, is an immunomodulatory cytokine that is highly expressed in the CNS. However, the role of IL-33 on viral encephalitis remains unclear. Therefore, we aimed to explore how the IL-33/ST2 axis regulates the local immune response during Rocio virus infection. Methods: Wild-type (WT), ST2 (ST2(-/-)), and nitric oxide synthase-deficient mice (iNOS(-/-)) and Stat6 (Stat6(-/-))-deficient mice were infected with different concentrations of the Rocio virus by intraperitoneal route, the cytokine mRNA level in CNS was analyzed by qPCR, and cellular immunophenotyping was performed on infected mice by the flow cytometry of isolated CNS mononuclear cells. Results: We have shown that the mRNA expression of IL-33 and ST2 receptors is increased in the CNS of Rocio virus-infected WT mice and that ST2(-/-) mice showed increased susceptibility to infection. ST2 deficiency was correlated with increased tissue pathology, cellular infiltration, and tumor necrosis factor alpha (TNF-alpha) and interferon-gamma (IFN-gamma) mRNA levels and higher viral load in the CNS, compared with wild-type mice. The increased Th1 cytokine levels released in the CNS acted on infiltrating macrophages, as evidenced by flow cytometry characterization of cellular infiltrates, inducing the expression of iNOS, contributing to brain injury. Moreover, iNOS(-/-) mice were more resistant to Rocio virus encephalitis, presenting a lower clinical score and reduced mortality rate, despite the increased tissue pathology. Conclusions: We provide evidences of a specific role for IL-33 receptor signaling in nitric oxide induction through local IFN-gamma modulation, suggesting that nitric oxide overproduction might have an important role in the progression of experimental viral encephalitis. (AU)

Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 11/19670-0 - Mecanismos envolvidos na fisiopatologia da artrite reumatóide, dor e sepse
Beneficiário:Fernando de Queiroz Cunha
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 10/19770-2 - Caracterização dos ligantes endógenos de NOD2 presentes no líquido sinovial de pacientes com artrite reumatoide
Beneficiário:Rafael Freitas de Oliveira Franca
Linha de fomento: Bolsas no Brasil - Pós-Doutorado