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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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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Author(s):
Lima-Junior, Djalma S. ; Mineo, Tiago W. P. ; Calich, Vera L. G. ; Zamboni, Dario S.
Total Authors: 4
Document type: Journal article
Source: JOURNAL OF IMMUNOLOGY; v. 199, n. 6, p. 2055-2068, SEP 15 2017.
Web of Science Citations: 21
Abstract

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)

FAPESP's process: 13/15994-1 - The role of NOD1 and NOD2 receptors in the control of Leishmania (L.) major infection
Grantee:Djalma de Souza Lima Júnior
Support type: Scholarships in Brazil - Post-Doctorate
FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
Grantee:Fernando de Queiroz Cunha
Support type: Research Grants - Research, Innovation and Dissemination Centers - RIDC
FAPESP's process: 14/04684-4 - The inflammasome in the host response against intracellular pathogens and the microbial mechanisms for its evasion
Grantee:Dario Simões Zamboni
Support type: Research Projects - Thematic Grants