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The NLRP3 inflammasome is activated in response to multiple stimuli and triggers activation of caspase-1 (CASP1), IL-1β production, and inflammation. NLRP3 activation requires two signals. The first leads to transcriptional regulation of specific genes related to inflammation, and the second is triggered when pathogens, toxins, or specific compounds damage cellular membranes and/or trigger the production of reactive oxygen species (ROS). Here, we assess the requirement of the first signal (priming) for the activation of the NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) infected with Leishmania amazonensis. We found that BMDMs express the inflammasome components NLRP3, ASC, and CASP1 at sufficient levels to enable the assembly and activation of NLRP3 inflammasome in response to infection. Therefore, priming was not required for the formation of ASC specks, CASP1 activation (measured by fluorescent dye FAM-YVAD), and restriction of L. amazonensis replication via the NLRP3 inflammasome. By contrast, BMDM priming was required for CASP1 cleavage (p20) and IL-1β secretion, because priming triggers robust up-regulation of pro-IL-1β and CASP11 that are important for efficient processing of CASP1 and IL-1β. Taken together, our data shed light into the cellular and molecular processes involved in activation of the NLRP3 in macrophages by Leishmania, a process that is important for the outcome of Leishmaniasis.
This article was published in the following journal.
Name: Journal of leukocyte biology
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A genus of flagellate protozoa comprising several species that are pathogenic for humans. Organisms of this genus have an amastigote and a promastigote stage in their life cycles. As a result of enzymatic studies this single genus has been divided into two subgenera: Leishmania leishmania and Leishmania viannia. Species within the Leishmania leishmania subgenus include: L. aethiopica, L. arabica, L. donovani, L. enrietti, L. gerbilli, L. hertigi, L. infantum, L. major, L. mexicana, and L. tropica. The following species are those that compose the Leishmania viannia subgenus: L. braziliensis, L. guyanensis, L. lainsoni, L. naiffi, and L. shawi.
An NLR protein that contains an N-terminal PYRIN DOMAIN and ATP-binding site and 9 C-terminal LEUCINE-rich repeats; it is expressed primarily by MACROPHAGES. It is a core component of the INFLAMMASOME and directs its assembly in response to pathogen infection and damage-associated stimuli. Mutations in the NLRP3 gene are associated with FAMILIAL COLD AUTOINFLAMMATORY SYNDROME.
A parasitic hemoflagellate of the subgenus Leishmania leishmania that has been found as a natural infection of the Brazilian guinea pig. Its host-tissue relationship is, in general, comparable to that of L. braziliensis.
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