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J Immunol. 2017 Sep 15;199(6):2055-2068. doi: 10.4049/jimmunol.1700258. Epub 2017 Aug 7.

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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Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil.
Institute of Biomedical Sciences, Federal University of Uberlândia, Uberlândia, Minas Gerais 38400-902, Brazil; and.
Department of Immunology, Institute of Biomedical Sciences, São Paulo University, São Paulo 05508-900, Brazil.
Department of Cell Biology, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14049-900, Brazil;


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.

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