Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of <i>Leishmania amazonensis</i> replication

Carvalho, Roberto Gameiro de; Silva, Alexandre L. N.; Santos, Leonardo Lima dos; Sá, Keyla Santos Guedes de; Zamboni, Dario S.

doi:10.1002/jlb.ma1118-471r

Cited by 19 publications

(10 citation statements)

References 50 publications

(106 reference statements)

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“…Importantly, inflammasome activation can only be robustly achieved upon previous priming (Supplementary Fig. 3a), just as observed in others studies 27,43,44 . The presence of the virus did not affect the production of inflammasome-independent cytokines, such as TNF-α (Fig.…”

Section: Resultssupporting

confidence: 72%

Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

et al. 2019

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Leishmania RNA virus (LRV) is an important virulence factor associated with the development of mucocutaneous Leishmaniasis, a severe form of the disease. LRV-mediated disease exacerbation relies on TLR3 activation, but downstream mechanisms remain largely unexplored. Here, we combine human and mouse data to demonstrate that LRV triggers TLR3 and TRIF to induce type I IFN production, which induces autophagy. This process results in ATG5mediated degradation of NLRP3 and ASC, thereby limiting NLRP3 inflammasome activation in macrophages. Consistent with the known restricting role of NLRP3 for Leishmania replication, the signaling pathway triggered by LRV results in increased parasite survival and disease progression. In support of this data, we find that lesions in patients infected with LRV+ Leishmania are associated with reduced inflammasome activation and the development of mucocutaneous disease. Our findings reveal the mechanisms triggered by LRV that contribute to the development of the debilitating mucocutaneous form of Leishmaniasis.

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Section: Resultssupporting

confidence: 72%

Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

et al. 2019

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“…The reason why the mRNA levels did not follow the protein levels was not clear, and previous studies have demonstrated similar results to ours 54 . Nevertheless, transcription‐independent roles of the priming signal have been recently shown 55 . LPS can prime the NLRP3 inflammasome activation independently of NLRP3 induction, once a short‐term pre‐treatment with LPS did not change NLRP3 expression 56 .…”

Section: Discussionmentioning

confidence: 99%

The role of annexin A1 in the modulation of the NLRP3 inflammasome

Galvão¹,

Carvalho²,

Vago³

et al. 2020

Immunology

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Annexins are well-known Ca 2+ phospholipid-binding proteins, which have a wide variety of cellular functions. The role of annexin A1 (AnxA1) in the innate immune system has focused mainly on the anti-inflammatory and proresolving properties through its binding to the formyl-peptide receptor 2 (FPR2)/ALX receptor. However, studies suggesting an intracellular role of AnxA1 are emerging. In this study, we aimed to understand the role of AnxA1 for interleukin (IL)-1b release in response to activators of the nucleotide-binding domain leucine-rich repeat (NLR) and pyrin domain containing receptor 3 (NLRP3) inflammasome. Using AnxA1 knockout mice, we observed that AnxA1 is required for IL-1b release in vivo and in vitro. These effects were due to reduction of transcriptional levels of IL-1b, NLRP3 and caspase-1, a step called NLRP3 priming. Moreover, we demonstrate that AnxA1 co-localize and directly bind to NLRP3, suggesting the role of AnxA1 in inflammasome activation is independent of its anti-inflammatory role via FPR2. Therefore, AnxA1 regulates NLRP3 inflammasome priming and activation in a FPR2-independent manner.Bone marrow-derived macrophages (BMDMs) were obtained as previously described. 31 Briefly, bone marrow cells were collected from femurs of wild-type (WT), AnxA1 À/À and FPR2/3 À/À mice and differentiated for 7 days in RPMI 1640 supplemented with 20% of fetal bovine serum (FBS) and 30% L929 conditioned medium.

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“…Interestingly, inflammasome assembly and signaling are closely associated with the physiopathology of leishmaniasis [ 30 – 32 ]. We and others have shown that the NLRP3 inflammasome is protective and contributes to restricting L. amazonensis parasite replication in macrophages as well as in vivo [ 30 , 33 , 34 ]. The canonical NLRP3 inflammasome promotes IL-1 β and IL-18 activation through the engagement of NLRP3, ASC, and caspase-1 activation.…”

Section: Discussionmentioning

confidence: 99%

P2Y2 Receptor Induces L. amazonensis Infection Control in a Mechanism Dependent on Caspase-1 Activation and IL-1β Secretion

Thorstenberg

Martins

Figliuolo

et al. 2020

Mediators of Inflammation

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Leishmaniasis is a neglected tropical disease caused by an intracellular parasite of the genus Leishmania. Damage-associated molecular patterns (DAMPs) such as UTP and ATP are released from infected cells and, once in the extracellular medium, activate P2 purinergic receptors. P2Y2 and P2X7 receptors cooperate to control Leishmania amazonensis infection. NLRP3 inflammasome activation and IL-1β release resulting from P2X7 activation are important for outcomes of L. amazonensis infection. The cytokine IL-1β is required for the control of intracellular parasites. In the present study, we investigated the involvement of the P2Y2 receptor in the activation of NLRP3 inflammasome elements (caspase-1 and 11) and IL-1β secretion during L. amazonensis infection in peritoneal macrophages as well as in a murine model of cutaneous leishmaniasis. We found that 2-thio-UTP (a selective P2Y2 agonist) reduced parasite load in L. amazonensis-infected murine macrophages and in the footpads and lymph nodes of infected mice. The antiparasitic effects triggered by P2Y2 activation were not observed when cells were pretreated with a caspase-1 inhibitor (Z-YVAD-FMK) or in macrophages from caspase-1/11 knockout mice (CASP-1,11−/−). We also found that UTP treatment induced IL-1β secretion in wild-type (WT) infected macrophages but not in cells from CASP-1,11−/− mice, suggesting that caspase-1 activation by UTP triggers IL-1β secretion in L. amazonensis-infected macrophages. Infected cells pretreated with IL-1R antagonist did not show reduced parasitic load after UTP and ATP treatment. Our in vivo experiments also showed that intralesional UTP treatment reduced both parasite load (in the footpads and popliteal lymph nodes) and lesion size in wild-type (WT) and CASP-11−/− but not in CASP-1,11−/− mice. Taken together, our findings suggest that P2Y2R activation induces CASP-1 activation and IL-1β secretion during L. amazonensis infection. IL-1β/IL-1R signaling is crucial for P2Y2R-mediated protective immune response in an experimental model of cutaneous leishmaniasis.

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Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication

Cited by 19 publications

References 50 publications

Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

Leishmania RNA virus exacerbates Leishmaniasis by subverting innate immunity via TLR3-mediated NLRP3 inflammasome inhibition

The role of annexin A1 in the modulation of the NLRP3 inflammasome

P2Y2 Receptor Induces L. amazonensis Infection Control in a Mechanism Dependent on Caspase-1 Activation and IL-1β Secretion

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