The Experts below are selected from a list of 19797 Experts worldwide ranked by ideXlab platform
Sergio Crovella - One of the best experts on this subject based on the ideXlab platform.
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nlrp1 and nlrp3 polymorphisms in mesothelioma patients and asbestos exposed individuals a population based autopsy study from north east italy
Infectious Agents and Cancer, 2015Co-Authors: Violetta Borelli, Ronald Moura, Elisa Trevisan, Sergio CrovellaAbstract:NRLP1 (rs12150220, rs9889625, rs9900356, rs6502867, rs2670660) and NLRP3 (rs35829419, rs10754558) polymorphisms have been analyzed in 69 subjects with documented asbestos exposure and death for malignant pleural mesothelioma and 59 patients with documented asbestos exposure but death for other causes, all from a North East Italy. No association was found between NLRP1 and NLRP3 polymorphisms and susceptibility to develop mesothelioma using the general, dominant or recessive models. Also haplotype analysis did not reveal any significant association with mesothelioma. Our findings, being controversial with respect to another study on Italian patients, do suggest the need of further studies to unravel the contribution of NLRP1 and NLRP3 in susceptibility to mesothelioma.
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nlrp1 haplotypes associated with leprosy in brazilian patients
Infection Genetics and Evolution, 2013Co-Authors: Alessandra Pontillo, Weber Laurentino, Sergio Crovella, Ana Carla PereiraAbstract:Abstract Polymorphisms in innate immunity genes are known to be involved in the multifactorial susceptibility to Mycobacterium leprae infection. M. leprae can downregulate IL-1β secretion escaping monocyte digestion. The intracellular receptors NLRPs (NACHT, LRR and PYD domains-containing proteins) sense pathogen associated molecular patterns (PAMPs) activating caspase-1 and IL-1β secretion in the context of inflammasome. Considering the possible role of inflammasome in the immune response against M. leprae, known single nucleotide polymorphisms (SNPs) in two NLRP genes, NLRP1 and NLRP3, were analyzed in Brazilian leprosy patients. Disease-associated SNPs (5 in NLRP1 and 2 in NLRP3), previously associated to infections and to immunologic disorders, were genotyped in 467 leprosy patients (327 multibacillary, MB; 96 paucibacillary, PB) and in 380 healthy controls (HC) from the state of Sao Paulo (Brazil), and in 183 patients (147 MB; 64 PB) and 186 HC from Mato Grosso (Brazil). Logistic regression analysis was performed considering susceptibility to leprosy di per se (leprosy versus HC) and clinical form (MB versus PB), adjusting for gender and ethnicity. Whereas none of the considered SNPs were statistically associated with leprosy, the NLRP1 combined haplotype rs2137722/G-rs12150220/T-rs2670660/G resulted significantly more frequent in patients than in HC as well as in PB than in MB. While both associations were lost after correction for gender and ethnicity, the NLRP1 combined haplotype rs2137722/G-rs12150220/A-rs2670660/G resulted strongly associated to PB. NLRP1 might be involved in the susceptibility to leprosy with particular emphasis for PB clinical form. Although preliminary, this is the first report linking NLRPs and inflammasome with leprosy: replication studies as well as functional assays are envisaged to deeper investigate the role of NLRP1 in M. leprae infection. Interestingly, NLRP1 SNPs were previously associated to susceptibility to Crohn disease, suggesting that NLRP1 could be a new modifier gene in common between leprosy and Crohn disease.
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bacterial lps differently modulates inflammasome gene expression and il 1β secretion in trophoblast cells decidual stromal cells and decidual endothelial cells
Reproductive Sciences, 2013Co-Authors: Alessandra Pontillo, Martina Girardelli, Chiara Agostinis, E Masat, Roberta Bulla, Sergio CrovellaAbstract:Three Nod-like receptors (NLR family, pyrin domain containing 1/NLRP1, NLR family, pyrin domain containing 3/NLRP3, NLR family, CARD domain containing 4/NLRC4) and the adaptor molecule PYD and CARD domain containing protein/PYCARD are involved in the assembling of multiprotein complexes known as inflammasomes, leading to caspase 1 activation and consequent interleukin (IL)-1β secretion. Considering that inflammasomes are involved in sensing pathogens and in triggering inflammatory and immune response, we hypothesized that they could also act in the placenta as an efficient innate mechanism during pregnancy infections. For this reason the activation of inflammasome was tested in 3 human placental cell populations in the presence of a common gram-negative compound (lipopolysaccharide [LPS]). The transcription of NLRP1, NLRP3, NLRC4, PYCARD, CASP1, and IL1B genes and the secretion of IL-1β were evaluated in human first trimester cytotrophoblasts (CTBs), decidual stromal cells (DSCs), and endothelial cells (DECs) stimulated with LPS. In CTBs and DSCs, LPS induced an augmented expression of CASP1 and IL1B and the specific upregulation of NLRP3 within the 3 NLRs tested. Moreover, LPS induced secretion of IL-1β from CTBs and DSCs. These results suggest the involvement of NLRP3 inflammasome in the placental innate response. The LPS did not affect inflammasome gene transcription and IL-1β production in DECs. Bacterial LPS enhances NLRP3 inflammasome components in trophoblast and DSCs, suggesting that this innate immune complex could play a key role in placental immune defense.
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nlrp1 polymorphisms in patients with asbestos associated mesothelioma
Infectious Agents and Cancer, 2012Co-Authors: Martina Girardelli, Iva Maestri, Rosa Rinaldi, Mauro Tognon, Renzo Boldorini, Massimo Bovenzi, Sergio Crovella, Manola ComarAbstract:Background An increasing incidence of malignant mesothelioma (MM) cases in patients with low levels of asbestos exposure suggests the interference of alternative cofactors. SV40 infection was detected, as co-morbidity factor, only in 22% of asbestos-MM patients from a North-Eastern Italy area. An additional mechanism of injury related to asbestos exposure in MM development has been recently associated to inflammatory responses, principally driven by interleukin (IL)-1 beta (s) activated within the inflammasome complex. NLRP3 inflammosome has been described as the intracellular sensor for asbestos able to induce inflammasome activation and IL-1s secretion while NLRP1 is expressed in lung epithelial cells and alveolar macrophages and contributes to the immune response and to survival/apoptosis balance. This study proposes to evaluate the impact of known NLRP3 and NLRP1 polymorphisms in the individual susceptibility to asbestos-induced mesothelioma in subjects from a hyperendemic area for MM.
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the missense variation q705k in cias1 nalp3 nlrp3 gene and an nlrp1 haplotype are associated with celiac disease
The American Journal of Gastroenterology, 2011Co-Authors: Alessandra Pontillo, Anna Vendramin, Eulalia Catamo, Annalisa Fabris, Sergio CrovellaAbstract:OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.
Alessandra Pontillo - One of the best experts on this subject based on the ideXlab platform.
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nlrp1 l155h polymorphism is a risk factor for preeclampsia development
American Journal of Reproductive Immunology, 2015Co-Authors: Alessandra Pontillo, Edione C Reis, Pamela N Bricher, Priscila Vianna, Solange Diniz, Karla Fernandes, Jose Artur Bogo Chies, Valeria C SandrimAbstract:Problem Augmented levels of IL-1s have been pointed out as an important pathogenic factor for preeclampsia development. Inflammasome is the cytoplasmic complex responsible for pro-IL1s cleavage and IL-1s secretion. Aim of the study was to evaluate the association between polymorphisms in inflammasome' genes and preeclampsia. Method of study Selected polymorphisms in inflammasome genes (NLRP1, NLRP3, CARD8, and IL1B) were analyzed in 286 Brazilian women with and 309 without preeclampsia. Results and Conlclusions The NLRP1 variant rs12150220 (L155H) was associated with the development of preeclampsia (OR = 1.58), suggesting a role of this inflammasome receptor in the pathogenesis of this multifactorial disorder.
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nlrp1 haplotypes associated with leprosy in brazilian patients
Infection Genetics and Evolution, 2013Co-Authors: Alessandra Pontillo, Weber Laurentino, Sergio Crovella, Ana Carla PereiraAbstract:Abstract Polymorphisms in innate immunity genes are known to be involved in the multifactorial susceptibility to Mycobacterium leprae infection. M. leprae can downregulate IL-1β secretion escaping monocyte digestion. The intracellular receptors NLRPs (NACHT, LRR and PYD domains-containing proteins) sense pathogen associated molecular patterns (PAMPs) activating caspase-1 and IL-1β secretion in the context of inflammasome. Considering the possible role of inflammasome in the immune response against M. leprae, known single nucleotide polymorphisms (SNPs) in two NLRP genes, NLRP1 and NLRP3, were analyzed in Brazilian leprosy patients. Disease-associated SNPs (5 in NLRP1 and 2 in NLRP3), previously associated to infections and to immunologic disorders, were genotyped in 467 leprosy patients (327 multibacillary, MB; 96 paucibacillary, PB) and in 380 healthy controls (HC) from the state of Sao Paulo (Brazil), and in 183 patients (147 MB; 64 PB) and 186 HC from Mato Grosso (Brazil). Logistic regression analysis was performed considering susceptibility to leprosy di per se (leprosy versus HC) and clinical form (MB versus PB), adjusting for gender and ethnicity. Whereas none of the considered SNPs were statistically associated with leprosy, the NLRP1 combined haplotype rs2137722/G-rs12150220/T-rs2670660/G resulted significantly more frequent in patients than in HC as well as in PB than in MB. While both associations were lost after correction for gender and ethnicity, the NLRP1 combined haplotype rs2137722/G-rs12150220/A-rs2670660/G resulted strongly associated to PB. NLRP1 might be involved in the susceptibility to leprosy with particular emphasis for PB clinical form. Although preliminary, this is the first report linking NLRPs and inflammasome with leprosy: replication studies as well as functional assays are envisaged to deeper investigate the role of NLRP1 in M. leprae infection. Interestingly, NLRP1 SNPs were previously associated to susceptibility to Crohn disease, suggesting that NLRP1 could be a new modifier gene in common between leprosy and Crohn disease.
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bacterial lps differently modulates inflammasome gene expression and il 1β secretion in trophoblast cells decidual stromal cells and decidual endothelial cells
Reproductive Sciences, 2013Co-Authors: Alessandra Pontillo, Martina Girardelli, Chiara Agostinis, E Masat, Roberta Bulla, Sergio CrovellaAbstract:Three Nod-like receptors (NLR family, pyrin domain containing 1/NLRP1, NLR family, pyrin domain containing 3/NLRP3, NLR family, CARD domain containing 4/NLRC4) and the adaptor molecule PYD and CARD domain containing protein/PYCARD are involved in the assembling of multiprotein complexes known as inflammasomes, leading to caspase 1 activation and consequent interleukin (IL)-1β secretion. Considering that inflammasomes are involved in sensing pathogens and in triggering inflammatory and immune response, we hypothesized that they could also act in the placenta as an efficient innate mechanism during pregnancy infections. For this reason the activation of inflammasome was tested in 3 human placental cell populations in the presence of a common gram-negative compound (lipopolysaccharide [LPS]). The transcription of NLRP1, NLRP3, NLRC4, PYCARD, CASP1, and IL1B genes and the secretion of IL-1β were evaluated in human first trimester cytotrophoblasts (CTBs), decidual stromal cells (DSCs), and endothelial cells (DECs) stimulated with LPS. In CTBs and DSCs, LPS induced an augmented expression of CASP1 and IL1B and the specific upregulation of NLRP3 within the 3 NLRs tested. Moreover, LPS induced secretion of IL-1β from CTBs and DSCs. These results suggest the involvement of NLRP3 inflammasome in the placental innate response. The LPS did not affect inflammasome gene transcription and IL-1β production in DECs. Bacterial LPS enhances NLRP3 inflammasome components in trophoblast and DSCs, suggesting that this innate immune complex could play a key role in placental immune defense.
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the missense variation q705k in cias1 nalp3 nlrp3 gene and an nlrp1 haplotype are associated with celiac disease
The American Journal of Gastroenterology, 2011Co-Authors: Alessandra Pontillo, Anna Vendramin, Eulalia Catamo, Annalisa Fabris, Sergio CrovellaAbstract:OBJECTIVES: Celiac disease (CD) is a multifactorial common disorder with several susceptibility loci. Variations in the NALP1/NLRP1 and NALP3/NLRP3 genes have been reported to confer risk for several autoimmune conditions. We hypothesized that polymorphisms in these genes, due to their role in innate immunity and inflammatory processes, may affect susceptibility to CD. METHODS: Two single-nucleotide polymorphisms (SNPs) in NLRP1 (rs12150220, rs2670660) and two SNPs (rs10754558, rs35829419) in NLRP3 genes were genotyped in 504 CD Italian patients and 256 healthy controls. RESULTS: The minor A allele of NLRP3 rs35829419 (Q705K) polymorphism appeared to exert a protective role against the development of CD (P=0.029; odds ratio (OR)=0.56). Moreover, a particular NLRP1 haplotype was associated with predisposition to CD (P=0.003; OR=1.38), even more when present in combination with the rs35829419 major C allele (P=0.002; OR=1.42). CONCLUSIONS: We hypothesized that the deregulation of CIAS1/NALP3/NLRP3 and NALP1/NLRP1 inflammasomes could have a role in CD pathogenesis.
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the missense variation q705k in cias1 nalp3 nlrp3 gene and an nlrp1 haplotype are associated with celiac disease
The American Journal of Gastroenterology, 2011Co-Authors: Alessandra Pontillo, Anna Vendramin, Eulalia Catamo, Annalisa Fabris, Sergio CrovellaAbstract:The Missense Variation Q705K in CIAS1 / NALP3 / NLRP3 Gene and an NLRP1 Haplotype Are Associated With Celiac Disease
Trinad Chakraborty - One of the best experts on this subject based on the ideXlab platform.
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listeria monocytogenes infected human peripheral blood mononuclear cells produce il 1β depending on listeriolysin o and nlrp3
Journal of Immunology, 2010Co-Authors: Karolin Meixenberger, Florence Pache, Julia Eitel, Bernd Schmeck, Stefan Hippenstiel, Hortense Slevogt, Philippe Dje Nguessan, Martin Witzenrath, Mihai G Netea, Trinad ChakrabortyAbstract:Different NOD-like receptors, including NLRP1, NLRP3, and NLRC4, as well as the recently identified HIN-200 protein, AIM2, form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. Listeria monocytogenes is an intracellular pathogen that is actively phagocytosed by monocytes/macrophages and subsequently escapes from the phagosome into the host cell cytosol, depending on its pore-forming toxin listeriolysin O (LLO). In this study, we demonstrate that human PBMCs produced mature IL-1beta when infected with wild-type L. monocytogenes or when treated with purified LLO. L. monocytogenes mutants lacking LLO or expressing a noncytolytic LLO as well as the avirulent Listeria innocua induced strongly impaired IL-1beta production. RNA interference and inhibitor experiments in human PBMCs as well as experiments in Nlrp3 and Rip2 knockout bone marrow-derived macrophages demonstrated that the Listeria-induced IL-1beta release was dependent on ASC, caspase-1, and NLRP3, whereas NOD2, Rip2, NLRP1, NLRP6, NLRP12, NLRC4, and AIM2 appeared to be dispensable. We found that L. monocytogenes-induced IL-1beta production was largely dependent on phagosomal acidification and cathepsin B release, whereas purified LLO activated an IL-1beta production independently of these mechanisms. Our results indicate that L. monocytogenes-infected human PBMCs produced IL-1beta, largely depending on an LLO-mediated phagosomal rupture and cathepsin B release, which is sensed by Nlrp3. In addition, an LLO-dependent but cathepsin B-independent NLRP3 activation might contribute to some extent to the IL-1beta production in L. monocytogenes-infected cells.
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listeria monocytogenes infected human peripheral blood mononuclear cells produce il 1beta depending on listeriolysin o and nlrp3
Journal of Immunology, 2010Co-Authors: Karolin Meixenberger, Florence Pache, Julia Eitel, Bernd Schmeck, Stefan Hippenstiel, Hortense Slevogt, Philippe Dje Nguessan, Martin Witzenrath, Mihai G Netea, Trinad ChakrabortyAbstract:Different NOD-like receptors, including NLRP1, NLRP3, and NLRC4, as well as the recently identified HIN-200 protein, AIM2, form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. Listeria monocytogenes is an intracellular pathogen that is actively phagocytosed by monocytes/macrophages and subsequently escapes from the phagosome into the host cell cytosol, depending on its pore-forming toxin listeriolysin O (LLO). In this study, we demonstrate that human PBMCs produced mature IL-1beta when infected with wild-type L. monocytogenes or when treated with purified LLO. L. monocytogenes mutants lacking LLO or expressing a noncytolytic LLO as well as the avirulent Listeria innocua induced strongly impaired IL-1beta production. RNA interference and inhibitor experiments in human PBMCs as well as experiments in Nlrp3 and Rip2 knockout bone marrow-derived macrophages demonstrated that the Listeria-induced IL-1beta release was dependent on ASC, caspase-1, and NLRP3, whereas NOD2, Rip2, NLRP1, NLRP6, NLRP12, NLRC4, and AIM2 appeared to be dispensable. We found that L. monocytogenes-induced IL-1beta production was largely dependent on phagosomal acidification and cathepsin B release, whereas purified LLO activated an IL-1beta production independently of these mechanisms. Our results indicate that L. monocytogenes-infected human PBMCs produced IL-1beta, largely depending on an LLO-mediated phagosomal rupture and cathepsin B release, which is sensed by Nlrp3. In addition, an LLO-dependent but cathepsin B-independent NLRP3 activation might contribute to some extent to the IL-1beta production in L. monocytogenes-infected cells.
Karolin Meixenberger - One of the best experts on this subject based on the ideXlab platform.
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listeria monocytogenes infected human peripheral blood mononuclear cells produce il 1β depending on listeriolysin o and nlrp3
Journal of Immunology, 2010Co-Authors: Karolin Meixenberger, Florence Pache, Julia Eitel, Bernd Schmeck, Stefan Hippenstiel, Hortense Slevogt, Philippe Dje Nguessan, Martin Witzenrath, Mihai G Netea, Trinad ChakrabortyAbstract:Different NOD-like receptors, including NLRP1, NLRP3, and NLRC4, as well as the recently identified HIN-200 protein, AIM2, form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. Listeria monocytogenes is an intracellular pathogen that is actively phagocytosed by monocytes/macrophages and subsequently escapes from the phagosome into the host cell cytosol, depending on its pore-forming toxin listeriolysin O (LLO). In this study, we demonstrate that human PBMCs produced mature IL-1beta when infected with wild-type L. monocytogenes or when treated with purified LLO. L. monocytogenes mutants lacking LLO or expressing a noncytolytic LLO as well as the avirulent Listeria innocua induced strongly impaired IL-1beta production. RNA interference and inhibitor experiments in human PBMCs as well as experiments in Nlrp3 and Rip2 knockout bone marrow-derived macrophages demonstrated that the Listeria-induced IL-1beta release was dependent on ASC, caspase-1, and NLRP3, whereas NOD2, Rip2, NLRP1, NLRP6, NLRP12, NLRC4, and AIM2 appeared to be dispensable. We found that L. monocytogenes-induced IL-1beta production was largely dependent on phagosomal acidification and cathepsin B release, whereas purified LLO activated an IL-1beta production independently of these mechanisms. Our results indicate that L. monocytogenes-infected human PBMCs produced IL-1beta, largely depending on an LLO-mediated phagosomal rupture and cathepsin B release, which is sensed by Nlrp3. In addition, an LLO-dependent but cathepsin B-independent NLRP3 activation might contribute to some extent to the IL-1beta production in L. monocytogenes-infected cells.
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listeria monocytogenes infected human peripheral blood mononuclear cells produce il 1beta depending on listeriolysin o and nlrp3
Journal of Immunology, 2010Co-Authors: Karolin Meixenberger, Florence Pache, Julia Eitel, Bernd Schmeck, Stefan Hippenstiel, Hortense Slevogt, Philippe Dje Nguessan, Martin Witzenrath, Mihai G Netea, Trinad ChakrabortyAbstract:Different NOD-like receptors, including NLRP1, NLRP3, and NLRC4, as well as the recently identified HIN-200 protein, AIM2, form multiprotein complexes called inflammasomes, which mediate caspase-1-dependent processing of pro-IL-1beta. Listeria monocytogenes is an intracellular pathogen that is actively phagocytosed by monocytes/macrophages and subsequently escapes from the phagosome into the host cell cytosol, depending on its pore-forming toxin listeriolysin O (LLO). In this study, we demonstrate that human PBMCs produced mature IL-1beta when infected with wild-type L. monocytogenes or when treated with purified LLO. L. monocytogenes mutants lacking LLO or expressing a noncytolytic LLO as well as the avirulent Listeria innocua induced strongly impaired IL-1beta production. RNA interference and inhibitor experiments in human PBMCs as well as experiments in Nlrp3 and Rip2 knockout bone marrow-derived macrophages demonstrated that the Listeria-induced IL-1beta release was dependent on ASC, caspase-1, and NLRP3, whereas NOD2, Rip2, NLRP1, NLRP6, NLRP12, NLRC4, and AIM2 appeared to be dispensable. We found that L. monocytogenes-induced IL-1beta production was largely dependent on phagosomal acidification and cathepsin B release, whereas purified LLO activated an IL-1beta production independently of these mechanisms. Our results indicate that L. monocytogenes-infected human PBMCs produced IL-1beta, largely depending on an LLO-mediated phagosomal rupture and cathepsin B release, which is sensed by Nlrp3. In addition, an LLO-dependent but cathepsin B-independent NLRP3 activation might contribute to some extent to the IL-1beta production in L. monocytogenes-infected cells.
Andréa C. Leblanc - One of the best experts on this subject based on the ideXlab platform.
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neuronal nlrp1 inflammasome activation of caspase 1 coordinately regulates inflammatory interleukin 1 beta production and axonal degeneration associated caspase 6 activation
Cell Death & Differentiation, 2015Co-Authors: Vikas Kaushal, Prateep Pakavathkumar, Bénédicte Foveau, Beverly H Koller, Bradley T Hyman, J. Flores, Bernardino Ghetti, Andréa C. LeblancAbstract:Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1−/− and Casp1−/− mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.
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neuronal nlrp1 inflammasome activation of caspase 1 coordinately regulates inflammatory interleukin 1 beta production and axonal degeneration associated caspase 6 activation
Cell Death & Differentiation, 2015Co-Authors: Vikas Kaushal, Prateep Pakavathkumar, Bénédicte Foveau, Beverly H Koller, Bradley T Hyman, J. Flores, Bernardino Ghetti, Andréa C. LeblancAbstract:Neuronal active Caspase-6 (Casp6) is associated with Alzheimer disease (AD), cognitive impairment, and axonal degeneration. Caspase-1 (Casp1) can activate Casp6 but the expression and functionality of Casp1-activating inflammasomes has not been well-defined in human neurons. Here, we show that primary cultures of human CNS neurons expressed functional Nod-like receptor protein 1 (NLRP1), absent in melanoma 2, and ICE protease activating factor, but not the NLRP3, inflammasome receptor components. NLRP1 neutralizing antibodies in a cell-free system, and NLRP1 siRNAs in neurons hampered stress-induced Casp1 activation. NLRP1 and Casp1 siRNAs also abolished stress-induced Casp6 activation in neurons. The functionality of the NLRP1 inflammasome in serum-deprived neurons was also demonstrated by NLRP1 siRNA-mediated inhibition of speck formation of the apoptosis-associated speck-like protein containing a caspase recruitment domain conjugated to green fluorescent protein. These results indicated a novel stress-induced intraneuronal NLRP1/Casp1/Casp6 pathway. Lipopolysaccharide induced Casp1 and Casp6 activation in wild-type mice brain cortex, but not in that of Nlrp1−/− and Casp1−/− mice. NLRP1 immunopositive neurons were increased 25- to 30-fold in AD brains compared with non-AD brains. NLRP1 immunoreactivity in these neurons co-localized with Casp6 activity. Furthermore, the NLRP1/Casp1/Casp6 pathway increased amyloid beta peptide 42 ratio in serum-deprived neurons. Therefore, CNS human neurons express functional NLRP1 inflammasomes, which activate Casp1 and subsequently Casp6, thus revealing a fundamental mechanism linking intraneuronal inflammasome activation to Casp1-generated interleukin-1-β-mediated neuroinflammation and Casp6-mediated axonal degeneration.