Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania

Lima-Júnior, Djalma S.; Costa, Diego L.; Carregaro, Vanessa; Cunha, Larissa D.; Silva, Alexandre L. N.; Mineo, Tiago Wilson Patriarca; Gutierrez, Fredy R. S.; Bellio, Maria; Bortoluci, Karina Ramalho; Flavell, Richard A.; Bozza, Marcelo T.; Silva, João; Zamboni, Dario S.

doi:10.1038/nm.3221

Cited by 330 publications

(420 citation statements)

References 48 publications

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“…Interestingly, only live P. brasiliensis efficiently induced the IL-1b release and caspase-1 maturation, indicating that virulence factors are necessary to generate the cellular damage recognized by the NLRs and cause caspase-1 activation. These data are similar to those from several other studies showing that live pathogens are required to activate caspase-1 (34). We then investigated the receptors and inflammasome components involved in P. brasiliensis-mediated caspase-1 activation and showed that Asc inflammasomes were required to promote IL1b induction during P. brasiliensis infection.…”

Section: Discussionsupporting

confidence: 86%

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Ketelut-Carneiro

Silva

Rocha

et al. 2015

The Journal of Immunology

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Pathogens are sensed by innate immune receptors that initiate an efficient adaptive immune response upon activation. The elements of the innate immune recognition process for Paracoccidioides brasiliensis include TLR-2, TLR-4, and dectin-1. However, there are additional receptors necessary for the host immune responses to P. brasiliensis. The nucleotide-binding oligomerization domain–like receptor (NLRs), which activate inflammasomes, are candidate receptors that deserve renewed investigation. After pathogen infection, the NLRs form large signaling platforms called inflammasomes, which lead to caspase-1 activation and maturation of proinflammatory cytokines (IL-18 and IL-1β). In this study, we showed that NLR family pyrin domain–containing 3 (Nlrp3) is required to induce caspase-1 activation and further secretion of IL-1β and IL-18 by P. brasiliensis–infected macrophages. Additionally, potassium efflux and lysosomal acidification induced by the fungus were important steps in the caspase-1 activation mechanism. Notably, Nlrp3 and caspase-1 knockout mice were more susceptible to infection than were the wild-type animals, suggesting that the Nlrp3-dependent inflammasomes contribute to host protection against P. brasiliensis. This protective effect occurred owing to the inflammatory response mediated by IL-18, as shown by an augmented fungus burden in IL-18 knockout mice. Taken together, our results show that the Nlrp3 inflammasome is essential for resistance against P. brasiliensis because it orchestrates robust caspase-1 activation and triggers an IL-18–dependent proinflammatory response.

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Section: Discussionsupporting

confidence: 86%

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

Ketelut-Carneiro

Silva

Rocha

et al. 2015

The Journal of Immunology

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“…Both imatinib (i.e. Abl family kinase inhibition alone) and PP2 decreased IL-1β levels, but based on previous studies, this decrease would not be expected to cause healing (Lima-Junior et al, 2013). PP2 also caused lower IFN-γ secretion at high antigenic stimulation (the opposite to what would be expected if the change were contributing to healing in PP2-treated mice; Soong et al, 2012) and decreased IL-17 secretion with Leishmania antigenic stimulation.…”

Section: Sfk and Dual Sfk And Arg Inhibitors Decrease Lesion Size Andmentioning

confidence: 96%

“…PP2 caused decreased secretion of MIP-1α, MIP-2 and CXCL9 (Table S3C), but these changes are not known to decrease BMDMs were incubated with opsonized promastigotes and amastigotes as described in Fig. 1 lesion size (Brandonisio et al, 2002;Lima-Junior et al, 2013;Muller et al, 2003;Oghumu et al, 2010;Ritter and Korner, 2002;Santiago et al, 2004). Given that bosutinib caused a significant inhibition of parasite uptake, and uptake is required for parasite survival, we suspected that the decreased cytokine secretion in bosutinib-treated mice resulted from lower parasite burdens in these mice.…”

Section: Sfk and Dual Sfk And Arg Inhibitors Decrease Lesion Size Andmentioning

confidence: 99%

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

Wetzel

Rhodes

et al. 2016

Journal of Cell Science

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Leishmaniasis is a devastating disease that disfigures or kills nearly two million people each year. Establishment and persistence of infection by the obligate intracellular parasite Leishmania requires repeated uptake by macrophages and other phagocytes. Therefore, preventing uptake could be a novel therapeutic strategy for leishmaniasis. Amastigotes, the life cycle stage found in the human host, bind Fc receptors and enter macrophages primarily through immunoglobulin-mediated phagocytosis. However, the host machinery that mediates amastigote uptake is poorly understood. We have previously shown that the Arg (also known as Abl2) nonreceptor tyrosine kinase facilitates L. amazonensis amastigote uptake by macrophages. Using small-molecule inhibitors and primary macrophages lacking specific Src family kinases, we now demonstrate that the Hck, Fgr and Lyn kinases are also necessary for amastigote uptake by macrophages. Src-mediated Arg activation is required for efficient uptake. Interestingly, the dual Arg and Src kinase inhibitor bosutinib, which is approved to treat cancer, not only decreases amastigote uptake, but also significantly reduces disease severity and parasite burden in Leishmania-infected mice. Our results suggest that leishmaniasis could potentially be treated with host-cellactive agents such as kinase inhibitors.

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“…3H). Interestingly, IL-1b was recently demonstrated to be critical for the restriction of Leishmania amazonensis infection (32). Because pyroptosis is required to control the replication of certain intracellular pathogens (33), we quantified this type of cell death in infected macrophages.…”

Section: T Cruzi Triggers Il-1b Productionmentioning

confidence: 99%

Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

Silva

Sesti-Costa

Silveira

et al. 2013

The Journal of Immunology

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The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain–like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1β and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck–like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain–containing 3 (NLRP3), but not NLR family, caspase recruitment domain–containing 4 or NLR family, pyrin domain–containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1β. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K+ efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-γ production in the heart, ASC−/− and caspase-1−/− infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.

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Inflammasome-derived IL-1β production induces nitric oxide–mediated resistance to Leishmania

Cited by 330 publications

References 48 publications

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

IL-18 Triggered by the Nlrp3 Inflammasome Induces Host Innate Resistance in a Pulmonary Model of Fungal Infection

The Src kinases Hck, Fgr, and Lyn activate Abl2/Arg to facilitate IgG-mediated phagocytosis andLeishmaniainfection

Apoptosis-Associated Speck–like Protein Containing a Caspase Recruitment Domain Inflammasomes Mediate IL-1β Response and Host Resistance to Trypanosoma cruzi Infection

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