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Dario S Zamboni - One of the best experts on this subject based on the ideXlab platform.
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gasdermin d and caspase 7 are the key caspase 1 8 substrates downstream of the naip5 NLRC4 inflammasome required for restriction of legionella pneumophila
PLOS Pathogens, 2019Co-Authors: Augusto V Goncalves, Russell E Vance, Isabella Rauch, Shally R Margolis, Gustavo F S Quirino, Danielle P A Mascarenhas, Randilea D Nichols, Eduard Ansaldo, Mary F Fontana, Dario S ZamboniAbstract:Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1–/– (and Casp1/11–/–) mice are only partially susceptible to L. pneumophila and do not phenocopy NLRC4–/–mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11–/– and Casp8/1/11–/– mice recapitulate the full susceptibility of NLRC4–/– mice. Gsdmd–/– mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd–/–Casp7–/– mice are as susceptible as the NLRC4–/– mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
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Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila.
PLOS Pathogens, 2019Co-Authors: Augusto V Goncalves, Russell E Vance, Isabella Rauch, Shally R Margolis, Gustavo F S Quirino, Danielle P A Mascarenhas, Randilea D Nichols, Eduard Ansaldo, Mary F Fontana, Dario S ZamboniAbstract:Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1–/– (and Casp1/11–/–) mice are only partially susceptible to L. pneumophila and do not phenocopy NLRC4–/–mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11–/– and Casp8/1/11–/– mice recapitulate the full susceptibility of NLRC4–/– mice. Gsdmd–/– mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd–/–Casp7–/– mice are as susceptible as the NLRC4–/– mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
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inhibition of caspase 1 or gasdermin d enable caspase 8 activation in the naip5 NLRC4 asc inflammasome
PLOS Pathogens, 2017Co-Authors: Danielle P A Mascarenhas, Daiane M Cerqueira, Marcelo S F Pereira, Fernanda V S Castanheira, Talita D Fernandes, Graziele Z Manin, Larissa D Cunha, Dario S ZamboniAbstract:Legionella pneumophila is a Gram-negative, flagellated bacterium that survives in phagocytes and causes Legionnaires’ disease. Upon infection of mammalian macrophages, cytosolic flagellin triggers the activation of Naip/NLRC4 inflammasome, which culminates in pyroptosis and restriction of bacterial replication. Although NLRC4 and caspase-1 participate in the same inflammasome, NLRC4-/- mice and their macrophages are more permissive to L. pneumophila replication compared with Casp1/11-/-. This feature supports the existence of a pathway that is NLRC4-dependent and caspase-1/11-independent. Here, we demonstrate that caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in response to flagellin-positive bacteria. Accordingly, caspase-8 is activated in Casp1/11-/- macrophages in a process dependent on flagellin, Naip5, NLRC4 and ASC. Silencing caspase-8 in Casp1/11-/- cells culminated in macrophages that were as susceptible as NLRC4-/- for the restriction of L. pneumophila replication. Accordingly, macrophages and mice deficient in Asc/Casp1/11-/- were more susceptible than Casp1/11-/- and as susceptible as NLRC4-/- for the restriction of infection. Mechanistically, we found that caspase-8 activation triggers gasdermin-D-independent pore formation and cell death. Interestingly, caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in wild-type macrophages, but it is only activated when caspase-1 or gasdermin-D is inhibited. Our data suggest that caspase-8 activation in the Naip5/NLRC4/ASC inflammasome enable induction of cell death when caspase-1 or gasdermin-D is suppressed.
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Inhibition of caspase-1 or gasdermin-D enable caspase-8 activation in the Naip5/NLRC4/ASC inflammasome
PLOS Pathogens, 2017Co-Authors: Danielle P A Mascarenhas, Daiane M Cerqueira, Marcelo S F Pereira, Fernanda V S Castanheira, Talita D Fernandes, Graziele Z Manin, Larissa D Cunha, Dario S ZamboniAbstract:Legionella pneumophila is a Gram-negative, flagellated bacterium that survives in phagocytes and causes Legionnaires’ disease. Upon infection of mammalian macrophages, cytosolic flagellin triggers the activation of Naip/NLRC4 inflammasome, which culminates in pyroptosis and restriction of bacterial replication. Although NLRC4 and caspase-1 participate in the same inflammasome, NLRC4-/- mice and their macrophages are more permissive to L. pneumophila replication compared with Casp1/11-/-. This feature supports the existence of a pathway that is NLRC4-dependent and caspase-1/11-independent. Here, we demonstrate that caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in response to flagellin-positive bacteria. Accordingly, caspase-8 is activated in Casp1/11-/- macrophages in a process dependent on flagellin, Naip5, NLRC4 and ASC. Silencing caspase-8 in Casp1/11-/- cells culminated in macrophages that were as susceptible as NLRC4-/- for the restriction of L. pneumophila replication. Accordingly, macrophages and mice deficient in Asc/Casp1/11-/- were more susceptible than Casp1/11-/- and as susceptible as NLRC4-/- for the restriction of infection. Mechanistically, we found that caspase-8 activation triggers gasdermin-D-independent pore formation and cell death. Interestingly, caspase-8 is recruited to the Naip5/NLRC4/ASC inflammasome in wild-type macrophages, but it is only activated when caspase-1 or gasdermin-D is inhibited. Our data suggest that caspase-8 activation in the Naip5/NLRC4/ASC inflammasome enable induction of cell death when caspase-1 or gasdermin-D is suppressed.
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caspase 1 but not caspase 11 is required for NLRC4 mediated pyroptosis and restriction of infection by flagellated legionella species in mouse macrophages and in vivo
Journal of Immunology, 2015Co-Authors: Daiane M Cerqueira, Marcelo S F Pereira, Larissa D Cunha, Alexandre L N Silva, Dario S ZamboniAbstract:Gram-negative bacteria from the Legionella genus are intracellular pathogens that cause a severe form of pneumonia called Legionnaires’ disease. The bacteria replicate intracellularly in macrophages, and the restriction of bacterial replication by these cells is critical for host resistance. The activation of the NAIP5/NLRC4 inflammasome, which is readily triggered in response to bacterial flagellin, is essential for the restriction of bacterial replication in murine macrophages. Once activated, this inflammasome induces pore formation and pyroptosis and facilitates the restriction of bacterial replication in macrophages. Because investigations related to the NLRC4-mediated restriction of Legionella replication were performed using mice double deficient for caspase-1 and caspase-11, we assessed the participation of caspase-1 and caspase-11 in the functions of the NLRC4 inflammasome and the restriction of Legionella replication in macrophages and in vivo. By using several species of Legionella and mice singly deficient for caspase-1 or caspase-11, we demonstrated that caspase-1 but not caspase-11 was required for pore formation, pyroptosis, and restriction of Legionella replication in macrophages and in vivo. By generating F 1 mice in a mixed 129 × C57BL/6 background deficient (129 × Casp-11 −/− ) or sufficient (129 × C57BL/6) for caspase-11 expression, we found that caspase-11 was dispensable for the restriction of Legionella pneumophila replication in macrophages and in vivo. Thus, although caspase-11 participates in flagellin-independent noncanonical activation of the NLRP3 inflammasome, it is dispensable for the activities of the NLRC4 inflammasome. In contrast, functional caspase-1 is necessary and sufficient to trigger flagellin/NLRC4-mediated restriction of Legionella spp. infection in macrophages and in vivo.
Rodrigue Dessein - One of the best experts on this subject based on the ideXlab platform.
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the human naip NLRC4 inflammasome senses the pseudomonas aeruginosa t3ss inner rod protein
International Immunology, 2017Co-Authors: Teddy Grandjean, Rodrigue Dessein, Anne Boucher, Marion Thepaut, Laura Monlezun, B Guery, Eric Faudry, Eric KipnisAbstract:While NLRC4-dependent sensing of intracellular Gram-negative pathogens such as Salmonella enterica serovar typhimurium is a beneficial host response, NLRC4-dependent sensing of the Pseudomonas aeruginosa type 3 secretion system (T3SS) has been shown to be involved in pathogenicity. In mice, different pathogen-associated microbial patterns are sensed by the combination of the NLRC4-inflammasome with different neuronal apoptosis inhibitory proteins (NAIPs). NAIP2 is involved in sensing PscI, an inner-rod protein of the P. aeruginosa T3SS. Surprisingly, only a single human NAIP (hNAIP) has been found. Moreover, there is no description of hNAIP-NLRC4 inflammasome recognition of T3SS inner-rod proteins in humans. Here, we show that the P. aeruginosa T3SS inner-rod protein PscI and needle protein PscF are both sensed by the hNAIP-NLRC4 inflammasome in human macrophages and PBMCs from healthy donors, allowing caspase-1 and IL-1β maturation and resulting in a robust inflammatory response. TLR4 and TLR2 are involved in redundantly sensing these two T3SS components.
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pseudomonas aeruginosa type 3 secretion system dampens host defense by exploiting the NLRC4 coupled inflammasome
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Emmanuel Faure, Jean Baptiste Mear, Sylvain Normand, Teddy Grandjean, Kevin Faure, Viviane Balloy, Rodrigue Dessein, Bernhard Ryffel, Aurelie Couturiermaillard, Michel ChignardAbstract:Rationale: Pseudomonas aeruginosa, a major problem pathogen responsible for severe infections in critically ill patients, triggers, through a functional type-3 secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4. Although the NLRC4-inflammasome–dependent response contributes to increased clearance of intracellular pathogens, it seems that NLRC4 inflammasome activation decreases the clearance of P. aeruginosa, a mainly extracellular pathogen.Objectives: We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa.Methods: We established acute lung injury in wild-type and NLRC4−/− mice using sublethal intranasal inocula of P. aeruginosa strain CHA expressing or not a functional T3SS. We studied 96-hour survival, lung injury, bacterial clearance from the lungs, cytokine secretion in bronchoalveolar lavage, lung antimicrobial peptide expression by quantitative polymerase chain reaction, and flow cytometry analysi...
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Pseudomonas aeruginosa type-3 secretion system dampens host defense by exploiting the NLRC4-coupled inflammasome
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Emmanuel Faure, Jean Baptiste Mear, Sylvain Normand, Aurélie Couturier-maillard, Teddy Grandjean, Kevin Faure, Viviane Balloy, Rodrigue Dessein, Bernhard Ryffel, Michel ChignardAbstract:Rationale. Pseudomonas aeruginosa, a major problem pathogen responsible for severe infections in critically ill patients, triggers, through a functional type-three secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4. While the NLRC4-inflammasome-dependent response contributes to increased clearance of intracellular pathogens, it seems that NLRC4-inflammasome activation decreases the clearance of P. aeruginosa, a mainly extracellular pathogen. Objectives. We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa. Methods. We established acute lung injury in both wild type and NLRC4-/- mice using sublethal intranasal inocula of P. aeruginosa strain CHA expressing or not a functional T3SS. We studied 96-hour survival, lung injury, bacterial clearance from the lungs, cytokine secretion in bronchoalveolar lavage, lung antimicrobial peptide expression by quantitative polymerase chain reaction and flow cytometry analysis of lung cells. Results. NLRC4-/- mice showed enhanced bacterial clearance and decreased lung injury contributing to increased survival against extracellular P. aeruginosa strain expressing a functional T3SS. The mechanism involved decreased NLRC4-inflammasome driven IL-18 secretion attenuating lung injury due to excessive neutrophil recruitment. Additionally, in the lungs of NLRC4-/- mice secretion of IL-17 by innate immune cells was increased and responsible for increased expression of lung epithelial antimicrobial peptides. Furthermore, IL-18 secretion was found to repress IL-17 and IL-17-driven lung antimicrobial peptide expression. Conclusion. We report a new role of the T3SS apparatus itself, independently of exotoxin translocation. Through NLRC4-inflammasome activation, the T3SS promotes IL-18 secretion, which dampens a beneficial IL-17-mediated antimicrobial host response.
Russell E Vance - One of the best experts on this subject based on the ideXlab platform.
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new mutant mouse models clarify the role of naips phosphorylation nlrp3 and tumors in NLRC4 inflammasome activation
bioRxiv, 2019Co-Authors: Jeannette L Tenthorey, Roberto A Chavez, Thornton W Thompson, Katherine A Deets, Russell E Vance, Isabella RauchAbstract:ABSTRACT The NAIP/NLRC4 inflammasome is a cytosolic sensor of bacteria that activates Caspase-1 and initiates potent downstream immune responses. Structural, biochemical, and genetic data all demonstrate that the NAIP proteins act as receptors for specific bacterial ligands, while NLRC4 is a downstream adaptor protein that multimerizes with NAIPs to form a macromolecular structure called an inflammasome. However, several aspects of NLRC4 biology remain unresolved. For example, in addition to its clear function in responding to bacteria, NLRC4 has also been proposed to initiate anti-tumor responses, though the underlying mechanism is unknown. NLRC4 has also been shown to be phosphorylated on serine 533, and this modification was suggested to be important for NLRC4 function. In the absence of S533 phosphorylation, it was further proposed that another inflammasome component, NLRP3, can induce NLRC4 activation. We generated a new NLRC4-deficient mouse line as well as mice encoding phosphomimetic S533D and non-phosphorylatable S533A NLRC4 proteins. Using these genetic models in vivo and in vitro, we fail to observe a role for phosphorylation in NLRC4 inflammasome function. Furthermore, we find no role for NLRP3 in NLRC4 function, or for NLRC4 in a model of melanoma. These results simplify and clarify our understanding of the mechanism of NAIP/NLRC4 activation and its biological functions.
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gasdermin d and caspase 7 are the key caspase 1 8 substrates downstream of the naip5 NLRC4 inflammasome required for restriction of legionella pneumophila
PLOS Pathogens, 2019Co-Authors: Augusto V Goncalves, Russell E Vance, Isabella Rauch, Shally R Margolis, Gustavo F S Quirino, Danielle P A Mascarenhas, Randilea D Nichols, Eduard Ansaldo, Mary F Fontana, Dario S ZamboniAbstract:Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1–/– (and Casp1/11–/–) mice are only partially susceptible to L. pneumophila and do not phenocopy NLRC4–/–mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11–/– and Casp8/1/11–/– mice recapitulate the full susceptibility of NLRC4–/– mice. Gsdmd–/– mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd–/–Casp7–/– mice are as susceptible as the NLRC4–/– mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
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Gasdermin-D and Caspase-7 are the key Caspase-1/8 substrates downstream of the NAIP5/NLRC4 inflammasome required for restriction of Legionella pneumophila.
PLOS Pathogens, 2019Co-Authors: Augusto V Goncalves, Russell E Vance, Isabella Rauch, Shally R Margolis, Gustavo F S Quirino, Danielle P A Mascarenhas, Randilea D Nichols, Eduard Ansaldo, Mary F Fontana, Dario S ZamboniAbstract:Inflammasomes are cytosolic multi-protein complexes that detect infection or cellular damage and activate the Caspase-1 (CASP1) protease. The NAIP5/NLRC4 inflammasome detects bacterial flagellin and is essential for resistance to the flagellated intracellular bacterium Legionella pneumophila. The effectors required downstream of NAIP5/NLRC4 to restrict bacterial replication remain unclear. Upon NAIP5/NLRC4 activation, CASP1 cleaves and activates the pore-forming protein Gasdermin-D (GSDMD) and the effector caspase-7 (CASP7). However, Casp1–/– (and Casp1/11–/–) mice are only partially susceptible to L. pneumophila and do not phenocopy NLRC4–/–mice, because NAIP5/NLRC4 also activates CASP8 for restriction of L. pneumophila infection. Here we show that CASP8 promotes the activation of CASP7 and that Casp7/1/11–/– and Casp8/1/11–/– mice recapitulate the full susceptibility of NLRC4–/– mice. Gsdmd–/– mice exhibit only mild susceptibility to L. pneumophila, but Gsdmd–/–Casp7–/– mice are as susceptible as the NLRC4–/– mice. These results demonstrate that GSDMD and CASP7 are the key substrates downstream of NAIP5/NLRC4/CASP1/8 required for resistance to L. pneumophila.
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cryo em studies of naip NLRC4 inflammasomes
Methods in Enzymology, 2019Co-Authors: Nicole Haloupek, Jeannette L Tenthorey, Russell E Vance, Patricia Grob, Eva NogalesAbstract:Abstract The NAIP–NLRC4 family of inflammasomes are components of the innate immune system that sound a molecular alarm in the presence of intracellular pathogens. In this chapter, we provide an in-depth guide to using cryo-electron microscopy (cryo-EM) to investigate these inflammasomes, focusing especially on the techniques we used in our recent structural analysis of the NAIP5–NLRC4 inflammasome. We explain how to circumvent specific obstacles we encountered at each step, from sample preparation through data processing. The methods described here will be useful for further studies of the NAIP5–NLRC4 inflammasome and related supracomplexes involved in innate immune surveillance; they may also be useful for unrelated complexes that present similar issues, such as preferential orientations and compositional heterogeneity.
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Cryo-EM studies of NAIP–NLRC4 inflammasomes
Methods in Enzymology, 2019Co-Authors: Nicole Haloupek, Jeannette L Tenthorey, Russell E Vance, Patricia Grob, Eva NogalesAbstract:Abstract The NAIP–NLRC4 family of inflammasomes are components of the innate immune system that sound a molecular alarm in the presence of intracellular pathogens. In this chapter, we provide an in-depth guide to using cryo-electron microscopy (cryo-EM) to investigate these inflammasomes, focusing especially on the techniques we used in our recent structural analysis of the NAIP5–NLRC4 inflammasome. We explain how to circumvent specific obstacles we encountered at each step, from sample preparation through data processing. The methods described here will be useful for further studies of the NAIP5–NLRC4 inflammasome and related supracomplexes involved in innate immune surveillance; they may also be useful for unrelated complexes that present similar issues, such as preferential orientations and compositional heterogeneity.
Wei Li - One of the best experts on this subject based on the ideXlab platform.
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overexpression of nlrp3 NLRC4 and aim2 inflammasomes and their priming associated molecules tlr2 tlr4 dectin 1 dectin 2 and nfκb in malassezia folliculitis
Mycoses, 2018Co-Authors: Ni Liang, Wei Li, Yanping Yang, Yayun Wu, Ziwei ZhangAbstract:Background The activation of NLRP3, NLRC4 and AIM2 inflammasomes is pivotal for innate immunity against some pathogenic fungi, but their role in the pathogenesis of Malassezia folliculitis (MF) remains unclear. Objectives To determine expression of four canonical inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) and their priming-associated molecules (TLR2, TLR4, Dectin-1, Dectin-2 and NFκB) in MF lesion. Methods Expression of NLRP1, NLRP3, NLRC4, AIM2, caspase-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2, and NFκB was detected by immunohistochemistry in skin lesion of 23 MF patients and normal skin of 12 healthy subjects. Furthermore, NLRP1, NLRP3, NLRC4, AIM2, caspase-1, and IL-1β mRNA was measured by quantitative real-time PCR (qRT-PCR) in 12 MF cases and 10 controls. Results Immunohistochemical analysis revealed that NLRP3, NLRC4, AIM2, Casp-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2, and NFκB expression was upregulated in the epidermis and dermal inflammatory cells of MF lesion compared with control skin (P 0.05). qRT-PCR showed that levels of NLRP3, Casp-1, and IL-1β mRNA were significantly increased (P 0.05). Conclusions Our observation suggests that simultaneous activation of NLRP3, NLRC4 and AIM2 inflammasomes may play an important role in the pathogenesis of MF. This article is protected by copyright. All rights reserved.
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Overexpression of NLRP3, NLRC4 and AIM2 inflammasomes and their priming‐associated molecules (TLR2, TLR4, Dectin‐1, Dectin‐2 and NFκB) in Malassezia folliculitis
Mycoses, 2017Co-Authors: Ni Liang, Wei Li, Yanping Yang, Yayun Wu, Ziwei ZhangAbstract:Background The activation of NLRP3, NLRC4 and AIM2 inflammasomes is pivotal for innate immunity against some pathogenic fungi, but their role in the pathogenesis of Malassezia folliculitis (MF) remains unclear. Objectives To determine expression of four canonical inflammasomes (NLRP1, NLRP3, NLRC4 and AIM2) and their priming-associated molecules (TLR2, TLR4, Dectin-1, Dectin-2 and NFκB) in MF lesion. Methods Expression of NLRP1, NLRP3, NLRC4, AIM2, caspase-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2, and NFκB was detected by immunohistochemistry in skin lesion of 23 MF patients and normal skin of 12 healthy subjects. Furthermore, NLRP1, NLRP3, NLRC4, AIM2, caspase-1, and IL-1β mRNA was measured by quantitative real-time PCR (qRT-PCR) in 12 MF cases and 10 controls. Results Immunohistochemical analysis revealed that NLRP3, NLRC4, AIM2, Casp-1, IL-1β, TLR2, TLR4, Dectin-1, Dectin-2, and NFκB expression was upregulated in the epidermis and dermal inflammatory cells of MF lesion compared with control skin (P 0.05). qRT-PCR showed that levels of NLRP3, Casp-1, and IL-1β mRNA were significantly increased (P 0.05). Conclusions Our observation suggests that simultaneous activation of NLRP3, NLRC4 and AIM2 inflammasomes may play an important role in the pathogenesis of MF. This article is protected by copyright. All rights reserved.
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obesity associated NLRC4 inflammasome activation drives breast cancer progression
Nature Communications, 2016Co-Authors: Ryan Kolb, Ann M. Janowski, Wei Li, Fang Yuan, Liem Phan, Nicholas Borcherding, Kathleen R Markan, Matthew J Potthoff, Enrique FuentesmatteiAbstract:Obesity is associated with an increased risk of developing breast cancer and is also associated with worse clinical prognosis. The mechanistic link between obesity and breast cancer progression remains unclear, and there has been no development of specific treatments to improve the outcome of obese cancer patients. Here we show that obesity-associated NLRC4 inflammasome activation/ interleukin (IL)-1 signalling promotes breast cancer progression. The tumour microenvironment in the context of obesity induces an increase in tumour-infiltrating myeloid cells with an activated NLRC4 inflammasome that in turn activates IL-1β, which drives disease progression through adipocyte-mediated vascular endothelial growth factor A (VEGFA) expression and angiogenesis. Further studies show that treatment of mice with metformin inhibits obesity-associated tumour progression associated with a marked decrease in angiogenesis. This report provides a causal mechanism by which obesity promotes breast cancer progression and lays out a foundation to block NLRC4 inflammasome activation or IL-1β signalling transduction that may be useful for the treatment of obese cancer patients.
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involvement of the NLRC4 inflammasome in diabetic nephropathy
PLOS ONE, 2016Co-Authors: Fayyaz S. Sutterwala, Wei Li, Fang Yuan, Ryan Kolb, Gaurav Pandey, Weizhou ZhangAbstract:Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease worldwide but current treatments remain suboptimal. The role of inflammation in DN has only recently been recognized. It has been shown that the NLRP3-inflammasome contributes to DN development by inducing interleukin (IL)-1β processing and secretion. In an effort to understand other IL-1β activating mechanism during DN development, we examined the role of the NLRC4-inflammasome in DN and found that NLRC4 is a parallel mechanism, in addition to the NLRP3-inflammasome, to induce pro-IL-1β processing and activation. We found that the expression of NLRC4 is elevated in DN kidneys. NLRC4-deficiency results in diminished DN disease progression, as manifested by a decrease in blood glucose and albumin excretion, as well as preserved renal histology. We further found that DN kidneys have increased F4/80+ macrophages, increased IL-1β production, and other signaling pathways related to kidney pathology such as activation of NF-κB and MAP kinase pathways, all of which were rescued by NLRC4-deficiency. This study demonstrates NLRC4-driven IL-1β production as critical for the progression of DN, which underscores the importance to target this pathway to alleviate this devastating disease.
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activation of NLRC4 downregulates tlr5 mediated antibody immune responses against flagellin
Cellular & Molecular Immunology, 2015Co-Authors: Wei Li, Jingyi Yang, Ejuan Zhang, Maohua Zhong, Yang Xiao, Jie Yu, Dihan Zhou, Yi Yang, Yaoming LiAbstract:Bacterial flagellin is a unique pathogen-associated molecular pattern (PAMP), which can be recognized by surface localized Toll-like receptor 5 (TLR5) and the cytosolic NOD-like receptor (NLR) protein 4 (NLRC4) receptors. Activation of the TLR5 and/or NLRC4 signaling pathways by flagellin and the resulting immune responses play important roles in anti-bacterial immunity. However, it remains unclear how the dual activities of flagellin that activate the TLR5 and/or NLRC4 signaling pathways orchestrate the immune responses. In this study, we assessed the effects of flagellin and its mutants lacking the ability to activate TLR5 and NLRC4 alone or in combination on the adaptive immune responses against flagellin. Flagellin that was unable to activate NLRC4 induced a significantly higher antibody response than did wild-type flagellin. The increased antibody response could be eliminated when macrophages were depleted in vivo. The activation of NLRC4 by flagellin downregulated the flagellin-induced and TLR5-mediated immune responses against flagellin.
Michel Chignard - One of the best experts on this subject based on the ideXlab platform.
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pseudomonas aeruginosa type 3 secretion system dampens host defense by exploiting the NLRC4 coupled inflammasome
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Emmanuel Faure, Jean Baptiste Mear, Sylvain Normand, Teddy Grandjean, Kevin Faure, Viviane Balloy, Rodrigue Dessein, Bernhard Ryffel, Aurelie Couturiermaillard, Michel ChignardAbstract:Rationale: Pseudomonas aeruginosa, a major problem pathogen responsible for severe infections in critically ill patients, triggers, through a functional type-3 secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4. Although the NLRC4-inflammasome–dependent response contributes to increased clearance of intracellular pathogens, it seems that NLRC4 inflammasome activation decreases the clearance of P. aeruginosa, a mainly extracellular pathogen.Objectives: We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa.Methods: We established acute lung injury in wild-type and NLRC4−/− mice using sublethal intranasal inocula of P. aeruginosa strain CHA expressing or not a functional T3SS. We studied 96-hour survival, lung injury, bacterial clearance from the lungs, cytokine secretion in bronchoalveolar lavage, lung antimicrobial peptide expression by quantitative polymerase chain reaction, and flow cytometry analysi...
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Pseudomonas aeruginosa type-3 secretion system dampens host defense by exploiting the NLRC4-coupled inflammasome
American Journal of Respiratory and Critical Care Medicine, 2014Co-Authors: Emmanuel Faure, Jean Baptiste Mear, Sylvain Normand, Aurélie Couturier-maillard, Teddy Grandjean, Kevin Faure, Viviane Balloy, Rodrigue Dessein, Bernhard Ryffel, Michel ChignardAbstract:Rationale. Pseudomonas aeruginosa, a major problem pathogen responsible for severe infections in critically ill patients, triggers, through a functional type-three secretion system (T3SS), the activation of an intracellular cytosolic sensor of innate immunity, NLRC4. While the NLRC4-inflammasome-dependent response contributes to increased clearance of intracellular pathogens, it seems that NLRC4-inflammasome activation decreases the clearance of P. aeruginosa, a mainly extracellular pathogen. Objectives. We sought to determine the underlying mechanisms of this effect of the activation of NLRC4 by P. aeruginosa. Methods. We established acute lung injury in both wild type and NLRC4-/- mice using sublethal intranasal inocula of P. aeruginosa strain CHA expressing or not a functional T3SS. We studied 96-hour survival, lung injury, bacterial clearance from the lungs, cytokine secretion in bronchoalveolar lavage, lung antimicrobial peptide expression by quantitative polymerase chain reaction and flow cytometry analysis of lung cells. Results. NLRC4-/- mice showed enhanced bacterial clearance and decreased lung injury contributing to increased survival against extracellular P. aeruginosa strain expressing a functional T3SS. The mechanism involved decreased NLRC4-inflammasome driven IL-18 secretion attenuating lung injury due to excessive neutrophil recruitment. Additionally, in the lungs of NLRC4-/- mice secretion of IL-17 by innate immune cells was increased and responsible for increased expression of lung epithelial antimicrobial peptides. Furthermore, IL-18 secretion was found to repress IL-17 and IL-17-driven lung antimicrobial peptide expression. Conclusion. We report a new role of the T3SS apparatus itself, independently of exotoxin translocation. Through NLRC4-inflammasome activation, the T3SS promotes IL-18 secretion, which dampens a beneficial IL-17-mediated antimicrobial host response.