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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.)

Dectin-1 Activation during Leishmania amazonensis Phagocytosis Prompts Syk-Dependent Reactive Oxygen Species Production To Trigger Inflammasome Assembly and Restriction of Parasite Replication

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Autor(es):
Lima-Junior, Djalma S. ; Mineo, Tiago W. P. ; Calich, Vera L. G. ; Zamboni, Dario S.
Número total de Autores: 4
Tipo de documento: Artigo Científico
Fonte: JOURNAL OF IMMUNOLOGY; v. 199, n. 6, p. 2055-2068, SEP 15 2017.
Citações Web of Science: 16
Resumo

Protozoan parasites of the genus Leishmania are the causative agents of Leishmaniasis, a disease that can be lethal and affects 12 million people worldwide. Leishmania replicates intracellularly in macrophages, a process that is essential for disease progression. Although the production of reactive oxygen species (ROS) accounts for restriction of parasite replication, Leishmania is known to induce ROS upon macrophage infection. We have recently demonstrated NLRP3 inflammasome activation in infected macrophages, a process that is important for the outcome of infection. However, the molecular mechanisms responsible for inflammasome activation are unknown. In this article, we demonstrate that ROS induced via NADPH oxidase during the early stages of L. amazonensis infection is critical for inflammasome activation in macrophages. We identified that ROS production during L. amazonensis infection occurs upon engagement of Dectin-1, a C-type lectin receptor that signals via spleen tyrosine kinase (Syk) to induce ROS. Accordingly, inflammasome activation in response to L. amazonensis is impaired by inhibitors of NADPH oxidase, Syk, focal adhesion kinase, and proline-rich tyrosine kinase 2, and in the absence of Dectin-1. Experiments performed with Clec7a(-/-) mice support the critical role of Dectin-1 for inflammasome activation, restriction of parasite replication in macrophages, and mouse resistance to L. amazonensis infection in vivo. Thus, we reported that activation of the Dectin-1/Syk/ ROS/NLRP3 pathway during L. amazonensis phagocytosis is important for macrophage restriction of the parasite replication and effectively accounts for host resistance to Leishmania infection. (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: 13/15994-1 - Papel dos receptores NOD1 e NOD2 no controle da infecção por Leishmania (L.) major
Beneficiário:Djalma de Souza Lima Júnior
Linha de fomento: Bolsas no Brasil - Pós-Doutorado
Processo FAPESP: 14/04684-4 - O inflamassoma na resposta contra patógenos intracelulares e os mecanismos microbianos relacionados à evasão
Beneficiário:Dario Simões Zamboni
Linha de fomento: Auxílio à Pesquisa - Temático