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Kristi L Williams - One of the best experts on this subject based on the ideXlab platform.
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NLRP12 REGULATES TLR2/DECTIN-1 FUNGAL RECEPTOR SIGNALING THROUGH ASSOCIATION WITH CARD9 (135.74)
Journal of Immunology, 2009Co-Authors: Christopher A Lord, Jo Rae Wright, Hisatsugu Goto, Joseph M. Thomas, Sambuddho Mukherjee, Hiroya Nambu, Robert A. Cramer, Xin Lin, Kristi L WilliamsAbstract:The NLR (nucleotide-binding domain, leucine-rich repeat) proteins are recently recognized as important intracellular regulators of host defense and immunity. One NLR gene, NLRP12/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in myeloid cells via regulation of TLRs and TNFR signal transduction. In contrast to its known role in regulating bacterial induced TLR activation of downstream genes, little is known about the role of NLRP12 in regulating the immune response to fungal pathogens. Here we show that NLRP12 modulates innate immune cellular responses to A. fumigatus by regulating TLR2/Dectin-1 fungal receptor signaling through its association with downstream signaling proteins CARD9 and Bcl10, but not Malt1. NLRP12, consisting of a pyrin, a nucleotide binding and a leucine rich repeat domain associates with the caspase recruitment domain containing proteins CARD9 and Bcl10 via the adaptor protein ASC. The most severe form of the NLRP12 disease associated mutant protein lacks the ability to associate with ASC, CARD9 and Bcl10 resulting in the lack of NLRP129s normal negative regulatory function. These data demonstrate the important role played by NLRP12 in modulating the innate immune response to fungal pathogens via its regulation of the TLR2/Dectin-1 induced CARD9 signaling pathway. This work was supported by NIH grants HL-30923 and HL-68072 (JRW), NIH COBRE grant RR020185 (RAC) a SERCEB award and funding from CCBVP to KLW.
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NLRP12 regulates tlr2 dectin 1 fungal receptor signaling through association with card9 135 74
Journal of Immunology, 2009Co-Authors: Christopher A Lord, Jo Rae Wright, Hisatsugu Goto, Joseph M. Thomas, Sambuddho Mukherjee, Hiroya Nambu, Robert A. Cramer, Xin Lin, Kristi L WilliamsAbstract:The NLR (nucleotide-binding domain, leucine-rich repeat) proteins are recently recognized as important intracellular regulators of host defense and immunity. One NLR gene, NLRP12/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in myeloid cells via regulation of TLRs and TNFR signal transduction. In contrast to its known role in regulating bacterial induced TLR activation of downstream genes, little is known about the role of NLRP12 in regulating the immune response to fungal pathogens. Here we show that NLRP12 modulates innate immune cellular responses to A. fumigatus by regulating TLR2/Dectin-1 fungal receptor signaling through its association with downstream signaling proteins CARD9 and Bcl10, but not Malt1. NLRP12, consisting of a pyrin, a nucleotide binding and a leucine rich repeat domain associates with the caspase recruitment domain containing proteins CARD9 and Bcl10 via the adaptor protein ASC. The most severe form of the NLRP12 disease associated mutant protein lacks the ability to associate with ASC, CARD9 and Bcl10 resulting in the lack of NLRP129s normal negative regulatory function. These data demonstrate the important role played by NLRP12 in modulating the innate immune response to fungal pathogens via its regulation of the TLR2/Dectin-1 induced CARD9 signaling pathway. This work was supported by NIH grants HL-30923 and HL-68072 (JRW), NIH COBRE grant RR020185 (RAC) a SERCEB award and funding from CCBVP to KLW.
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blimp 1 prdm1 mediates transcriptional suppression of the nlr gene NLRP12 monarch 1
Journal of Immunology, 2009Co-Authors: Christopher A Lord, David Savitsky, Raquel Sitcheran, Kathryn Calame, Jo Rae Wright, Jenny P Y Ting, Kristi L WilliamsAbstract:NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/ Monarch-1 , has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1 −/− murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene.
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Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1
The Journal of Immunology, 2009Co-Authors: Christopher A Lord, David Savitsky, Raquel Sitcheran, Kathryn Calame, Jo Rae Wright, Jenny P Y Ting, Kristi L WilliamsAbstract:NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/ Monarch-1 , has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1 −/− murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene.
Serge Amselem - One of the best experts on this subject based on the ideXlab platform.
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Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes.
Arthritis & Rheumatism, 2011Co-Authors: Isabelle Jéru, Gaëlle Le Borgne, Emmanuelle Cochet, Hasmik Hayrapetyan, Philippe Duquesnoy, Gilles Grateau, A. Morali, Tamara Sarkisian, Serge AmselemAbstract:Objective To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation. Methods NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-κB activation. Results A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD). Conclusion Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS.
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Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes.
Arthritis and rheumatism, 2011Co-Authors: Isabelle Jéru, Gaëlle Le Borgne, Emmanuelle Cochet, Hasmik Hayrapetyan, Philippe Duquesnoy, Gilles Grateau, A. Morali, Tamara Sarkisian, Serge AmselemAbstract:To gain insight into the molecular bases of genetically unexplained periodic fever syndromes (PFS) by screening NLRP12, a gene in which only a nonsense and a splice site mutation have so far been identified, and to assess the functional consequences of the identified missense variation. NLRP12 was screened for mutations by direct sequencing. Functional assays were performed in HEK 293T cells stably expressing the proapoptotic protein ASC and procaspase 1, in order to determine the effects of normal and mutated NLRP12 proteins on speck formation, caspase 1 signaling, and NF-κB activation. A heterozygous NLRP12 missense mutation involving a CpG site (c.1054C>T; p.Arg352Cys) was identified in exon 3, which encodes the nucleotide-binding site (NBS) of the protein, in 2 patients from different countries and carrying different NLRP12 haplotypes. The mutation, which does not alter the inhibitory effect of NLRP12 on NF-κB activation, increases speck formation and activates caspase 1 signaling. To define this new class of PFS, we propose the term NLRP12-associated disorders (NLRP12AD). Given the rarity of known NLRP12-associated disorders, the identification of this NLRP12 molecular defect contributes to the delineation of the clinical spectrum associated with mutations in this gene and highlights the importance of screening NLRP12 in patients presenting with unexplained PFS. This study also demonstrates, by means of functional assays, the deleterious effect of this recurrent missense mutation; the gain of function for speck formation and caspase 1 signaling associated with this NBS mutation is consistent with the inflammatory phenotype of PFS. Copyright © 2011 by the American College of Rheumatology.
Christopher A Lord - One of the best experts on this subject based on the ideXlab platform.
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NLRP12 REGULATES TLR2/DECTIN-1 FUNGAL RECEPTOR SIGNALING THROUGH ASSOCIATION WITH CARD9 (135.74)
Journal of Immunology, 2009Co-Authors: Christopher A Lord, Jo Rae Wright, Hisatsugu Goto, Joseph M. Thomas, Sambuddho Mukherjee, Hiroya Nambu, Robert A. Cramer, Xin Lin, Kristi L WilliamsAbstract:The NLR (nucleotide-binding domain, leucine-rich repeat) proteins are recently recognized as important intracellular regulators of host defense and immunity. One NLR gene, NLRP12/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in myeloid cells via regulation of TLRs and TNFR signal transduction. In contrast to its known role in regulating bacterial induced TLR activation of downstream genes, little is known about the role of NLRP12 in regulating the immune response to fungal pathogens. Here we show that NLRP12 modulates innate immune cellular responses to A. fumigatus by regulating TLR2/Dectin-1 fungal receptor signaling through its association with downstream signaling proteins CARD9 and Bcl10, but not Malt1. NLRP12, consisting of a pyrin, a nucleotide binding and a leucine rich repeat domain associates with the caspase recruitment domain containing proteins CARD9 and Bcl10 via the adaptor protein ASC. The most severe form of the NLRP12 disease associated mutant protein lacks the ability to associate with ASC, CARD9 and Bcl10 resulting in the lack of NLRP129s normal negative regulatory function. These data demonstrate the important role played by NLRP12 in modulating the innate immune response to fungal pathogens via its regulation of the TLR2/Dectin-1 induced CARD9 signaling pathway. This work was supported by NIH grants HL-30923 and HL-68072 (JRW), NIH COBRE grant RR020185 (RAC) a SERCEB award and funding from CCBVP to KLW.
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NLRP12 regulates tlr2 dectin 1 fungal receptor signaling through association with card9 135 74
Journal of Immunology, 2009Co-Authors: Christopher A Lord, Jo Rae Wright, Hisatsugu Goto, Joseph M. Thomas, Sambuddho Mukherjee, Hiroya Nambu, Robert A. Cramer, Xin Lin, Kristi L WilliamsAbstract:The NLR (nucleotide-binding domain, leucine-rich repeat) proteins are recently recognized as important intracellular regulators of host defense and immunity. One NLR gene, NLRP12/Monarch-1, has emerged as an important inhibitor of inflammatory gene expression in myeloid cells via regulation of TLRs and TNFR signal transduction. In contrast to its known role in regulating bacterial induced TLR activation of downstream genes, little is known about the role of NLRP12 in regulating the immune response to fungal pathogens. Here we show that NLRP12 modulates innate immune cellular responses to A. fumigatus by regulating TLR2/Dectin-1 fungal receptor signaling through its association with downstream signaling proteins CARD9 and Bcl10, but not Malt1. NLRP12, consisting of a pyrin, a nucleotide binding and a leucine rich repeat domain associates with the caspase recruitment domain containing proteins CARD9 and Bcl10 via the adaptor protein ASC. The most severe form of the NLRP12 disease associated mutant protein lacks the ability to associate with ASC, CARD9 and Bcl10 resulting in the lack of NLRP129s normal negative regulatory function. These data demonstrate the important role played by NLRP12 in modulating the innate immune response to fungal pathogens via its regulation of the TLR2/Dectin-1 induced CARD9 signaling pathway. This work was supported by NIH grants HL-30923 and HL-68072 (JRW), NIH COBRE grant RR020185 (RAC) a SERCEB award and funding from CCBVP to KLW.
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blimp 1 prdm1 mediates transcriptional suppression of the nlr gene NLRP12 monarch 1
Journal of Immunology, 2009Co-Authors: Christopher A Lord, David Savitsky, Raquel Sitcheran, Kathryn Calame, Jo Rae Wright, Jenny P Y Ting, Kristi L WilliamsAbstract:NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/ Monarch-1 , has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1 −/− murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene.
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Blimp-1/PRDM1 Mediates Transcriptional Suppression of the NLR Gene NLRP12/Monarch-1
The Journal of Immunology, 2009Co-Authors: Christopher A Lord, David Savitsky, Raquel Sitcheran, Kathryn Calame, Jo Rae Wright, Jenny P Y Ting, Kristi L WilliamsAbstract:NLR (nucleotide-binding domain, leucine-rich repeat) proteins are intracellular regulators of host defense and immunity. One NLR gene, NLRP12 (NLR family, pyrin domain containing 12)/ Monarch-1 , has emerged as an important inhibitor of inflammatory gene expression in human myeloid cells. This is supported by genetic analysis linking the loss of a functional NLRP12 protein to hereditary periodic fever. NLRP12 transcription is diminished by specific TLR stimulation and myeloid cell maturation, consistent with its role as a negative regulator of inflammation. The NLRP12 promoter contains a novel Blimp-1 (B lymphocyte-induced maturation protein-1)/PRDM1 (PR domain-containing 1, with ZNF domain) binding site, and Blimp-1 reduces NLRP12 promoter activity, expression, and histone 3 acetylation. Blimp-1 associates with the endogenous NLRP12 promoter in a TLR-inducible manner and mediates the down-regulation of NLRP12 expression by TLR agonists. As expected, the expression of NLRP12 and Blimp-1 is inversely correlated. Analysis of Blimp-1 −/− murine myeloid cells provides physiologic evidence that Blimp-1 reduces NLRP12 gene expression during cell differentiation. This demonstrates a novel role for Blimp-1 in the regulation of an NLR gene.
Hongmei Song - One of the best experts on this subject based on the ideXlab platform.
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THU0516 FIFTEEN CASES OF 3 NLR FAMILY MEMBERS (NLRP3, NLRP12 AND NLRC4) RELATED INFLAMMASOMOPATHIES IN A SINGLE CENTER OF CHINA
Annals of the Rheumatic Diseases, 2020Co-Authors: Wei Wang, Yu Zhou, Hongmei SongAbstract:Background:There are four members in NLR family, NLRP3, NLRC4, NLRP1, and NLRP12, the mutations of which can lead to autoinflammatory diseases, while little reports describe those diseases in Chinese population.Objectives:To report several cases of NLR-related autoinflammatory diseases in our center and to compare the differences of the presentations of CAPS between Chinese and western patients.Methods:This study was undertaken at Peking Union Medical College Hospital (PUMCH) between 2012 and 2019. Demographic data, clinical presentations and genetic results were collected.Results:15 patients had been diagnosed as NLR-related autoinflammatory diseases in our center, including 11 CAPS, 1 FCAS4 and 3 NLRP12-AD patients.We found 10 NLRP3 mutations, 3 NLRP12 mutations and 1 NLRC4 mutation. There are 3 novel mutations: NLRP3 c.1311G>T, NLRP3 c.1711G>A, and NLRC4 c.514G>A.The major symptoms of those diseases are similar, such as recurrent episodes of fever associated with rash. And some may suffer from arthritis/arthralgia, uveitis, sensorineural deafness, symptoms of central neural systems (CNS).On the other hand, different inflammasomopathies have unique characteristics. Symptoms of FCAS1, the mildest CAPS disorder, including rash and fever with/without arthritis/arthralgia, usually develop in the first year of life. The onset age of MWS is later (8m to 5y), and those patients were more likely to develop arthritis/arthralgia, eye involvement, hearing loss and symptoms of CNS. NOMID was the most severe type, and was presented with chronic urticarial-like rash shortly after birth, as well as severe CNS manifestations and musculoskeletal involvement. One of our NOMID patients had clubbing fingers, which was not reported before. The onset age of NLRP12-AD ranges from 6m to 5y and the presentation is similar to MWS while the FCAS4 patient presented with rash and fever, like FCAS1.For laboratory examinations, all patients had raised inflammatory markers like ESR or CRP. Most of those patients had increased cytokines, including IL-1β, IL-6 as well as TNF-α. Leukocytosis and thrombocytosis were also observed in most patients, while anemia was mostly found in patients diagnosed as NOMID.We also compared the clinical manifestations of CAPS between Chinese and western patients. The frequency of fever in Chinese is much higher than that in western population, while less Chinese patients suffered from ocular manifestations. Besides, Chinese patients seem to exhibit higher frequencies of severe symptoms, either CNS symptoms, or musculoskeletal symptoms, albeit with insignificant difference.ChineseWesternp valuen26136Gender Ratio15:1169:670.518Fever25/26 (96%)108 (79%)0.002Rash24/26 (92%)132 (97%)0.397 Triggered by cold3/26 (12%)34 (25%)0.076Ocular manifestations10/26 (38%)97 (71%)0.001Hearing loss9/26 (35%)56 (41%)0.535Neurological symptoms15/26 (58%)55 (40%)0.105 Severe4/11 (36%)16 (12%)0.141Musculoskeletal manifestations18/26 (69%)117 (86%)0.093 Severe3/11 (27%)6 (4%)0.137Increased CRP/ESR25/26 (96%)NAConclusion:We reported a case series of NLR-related autoinflammatory disease and found some novel mutated alleles and clinical phenotypes, which expanded our knowledge to those diseases. By comparing clinical manifestations of CAPS patients in China and in western countries, it seems that the symptoms in different populations are not identical.References:[1]Levy R, Gerard L, Kuemmerle-Deschner J, Lachmann HJ, Kone-Paut I, Cantarini L et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis. 2015;74(11):2043-9.[2]Li C, Tan X, Zhang J, Li S, Mo W, Han T et al. Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin-associated periodic syndrome (CAPS). Sci China Life Sci. 2017;60(12):1436-44.Acknowledgments:We’d like to thank the patients as well as their parents for their participation.Disclosure of Interests:None declared
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THU0516 FIFTEEN CASES OF 3 NLR FAMILY MEMBERS (NLRP3, NLRP12 AND NLRC4) RELATED INFLAMMASOMOPATHIES IN A SINGLE CENTER OF CHINA
Annals of the Rheumatic Diseases, 2020Co-Authors: Wei Wang, Yu Zhou, Hongmei SongAbstract:Background: There are four members in NLR family, NLRP3, NLRC4, NLRP1, and NLRP12, the mutations of which can lead to autoinflammatory diseases, while little reports describe those diseases in Chinese population. Objectives: To report several cases of NLR-related autoinflammatory diseases in our center and to compare the differences of the presentations of CAPS between Chinese and western patients. Methods: This study was undertaken at Peking Union Medical College Hospital (PUMCH) between 2012 and 2019. Demographic data, clinical presentations and genetic results were collected. Results: 15 patients had been diagnosed as NLR-related autoinflammatory diseases in our center, including 11 CAPS, 1 FCAS4 and 3 NLRP12-AD patients. We found 10 NLRP3 mutations, 3 NLRP12 mutations and 1 NLRC4 mutation. There are 3 novel mutations: NLRP3 c.1311G>T, NLRP3 c.1711G>A, and NLRC4 c.514G>A. The major symptoms of those diseases are similar, such as recurrent episodes of fever associated with rash. And some may suffer from arthritis/arthralgia, uveitis, sensorineural deafness, symptoms of central neural systems (CNS). On the other hand, different inflammasomopathies have unique characteristics. Symptoms of FCAS1, the mildest CAPS disorder, including rash and fever with/without arthritis/arthralgia, usually develop in the first year of life. The onset age of MWS is later (8m to 5y), and those patients were more likely to develop arthritis/arthralgia, eye involvement, hearing loss and symptoms of CNS. NOMID was the most severe type, and was presented with chronic urticarial-like rash shortly after birth, as well as severe CNS manifestations and musculoskeletal involvement. One of our NOMID patients had clubbing fingers, which was not reported before. The onset age of NLRP12-AD ranges from 6m to 5y and the presentation is similar to MWS while the FCAS4 patient presented with rash and fever, like FCAS1. For laboratory examinations, all patients had raised inflammatory markers like ESR or CRP. Most of those patients had increased cytokines, including IL-1β, IL-6 as well as TNF-α. Leukocytosis and thrombocytosis were also observed in most patients, while anemia was mostly found in patients diagnosed as NOMID. We also compared the clinical manifestations of CAPS between Chinese and western patients. The frequency of fever in Chinese is much higher than that in western population, while less Chinese patients suffered from ocular manifestations. Besides, Chinese patients seem to exhibit higher frequencies of severe symptoms, either CNS symptoms, or musculoskeletal symptoms, albeit with insignificant difference. Conclusion: We reported a case series of NLR-related autoinflammatory disease and found some novel mutated alleles and clinical phenotypes, which expanded our knowledge to those diseases. By comparing clinical manifestations of CAPS patients in China and in western countries, it seems that the symptoms in different populations are not identical. References: [1]Levy R, Gerard L, Kuemmerle-Deschner J, Lachmann HJ, Kone-Paut I, Cantarini L et al. Phenotypic and genotypic characteristics of cryopyrin-associated periodic syndrome: a series of 136 patients from the Eurofever Registry. Ann Rheum Dis. 2015;74(11):2043-9. [2]Li C, Tan X, Zhang J, Li S, Mo W, Han T et al. Gene mutations and clinical phenotypes in 15 Chinese children with cryopyrin-associated periodic syndrome (CAPS). Sci China Life Sci. 2017;60(12):1436-44. Acknowledgments: We’d like to thank the patients as well as their parents for their participation. Disclosure of Interests: None declared
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The clinical phenotype and genotype of NLRP12-autoinflammatory disease: a Chinese case series with literature review.
World Journal of Pediatrics, 2019Co-Authors: Wei Wang, Linqing Zhong, Yu Zhou, Shan Jian, Xiaoyan Tang, Hongmei SongAbstract:The nucleotide-binding oligomerization domain-like receptor protein 12 (NLRP12)-autoinflammatory disorder (NLRP12-AD) is a rare autoinflammatory disease characterized by recurrent fever, rash as well as musculoskeletal symptoms, which is rarely reported in Asian populations. Three cases of NLRP12-AD presented to our hospital were studied after parental consents were obtained. Clinical presentations were recorded on a standardized case report form. Mutations of NLRP12 were detected by primary immunodeficiency disease panels and further examined by Sanger sequencing. PubMed literature search for relevant studies of systemic autoinflammatory disorders, especially NLRP12-AD between January, 2000 and January, 2019 was carried and the clinical data were summarized. Comparisons were made between groups in terms of onset age and of ethnicity. All our patients presented with fever, rash and arthritis/arthralgia, and sensorineural as well as sensorineural deafness (1/3), uveitis (1/3), abdominal pain (1/3), and myalgia (1/3). Two novel mutation variations, p.W581X and p.L558R, are reported here. In addition, we also found that two patients inherited the mutated alleles from their healthy parents, and this may be evidence of haploinsufficiency. Although the genotypes are similar, the clinical manifestations between Chinese patients and Western patients vary thus highlighting the possible influence of ethnic and environmental factors. On the other hand, some genetic mutations may lead to specific phenotype, as we have found a high prevalence of sensorineural hearing loss among p.R284X patients.
Hasan Zaki - One of the best experts on this subject based on the ideXlab platform.
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abstract 2732 NLRP12 suppresses colorectal cancer progression and invasion via downregulation of the wnt b catenin pathway
Cancer Research, 2020Co-Authors: Shahanshah Khan, Hasan ZakiAbstract:Metastatic CRC is associated with increased mortality, underscoring the importance of understanding the molecular mechanism of CRC invasion and metastasis. We recently demonstrated that mice deficient in NLRP12, an innate immune sensor, are susceptible to CRC with increased incidence of invasive adenocarcinoma. Here, we investigated the molecular mechanism of NLRP12-mediated suppression of cancer progression and invasion using mouse models and in vitro biochemical studies. NLRP12−/− mice treated with azoxymethane plus dextran sodium sulfate developed higher tumor burden and invasive adenocarcinoma compared to WT mice. RNA-seq analysis showed significantly higher levels of protooncogenes, matrix metalloproteinases (Mmp 3, 7,8, 10, 12), and epithelial to mesenchymal transition (EMT) markers (Vim, Fn1, Foxc2, Zeb2, Ezh2) in NLRP12−/− tumors. To understand the underlying mechanism of increased expression of cancer promoting genes in NLRP12−/− tumors, we analyzed activation of various cell signaling pathways. To our surprise, there was no major difference in the activation NF-κB, ERK, JNK, and STAT3, which have previously been shown to be downregulated by NLRP12, between WT and NLRP12−/- tumors. However, we observed strikingly higher levels of β-catenin and expression of Wnt target genes (Ctnnb1, Axin2, Yap1, Tcf3, Lgr5, etc.) in NLRP12−/− tumors. Consistently, deletion of NLRP12 in APCmin/+ mice led to higher polyp development and activation of the Wnt/β-catenin pathway. Notably, hyperactivation of the Wnt/β-catenin pathway is a hallmark of CRC and about 80% of CRC patients carry mutations in the Wnt/β-catenin pathway. To further explore the link between NLRP12 and the Wnt/β-catenin pathway, we overexpressed NLRP12 in HEK293T cells and CRC cell line MC38. NLRP12-overexpressed cells showed reduced activation of β-catenin and expression of Wnt target genes following stimulation with Wnt3a. An opposite result was observed when NLRP12 was knocked out from these cell lines. Consistently, NLRP12-KO MC38 cells exhibited increased proliferation, colony formation, and migration. These data for the first time demonstrate that NLRP12 is an intrinsic negative regulator of the Wnt/β-catenin pathway. Overall, these findings reveal a novel CRC suppression pathway involving NLRP12 and suggest that the NLRP12/β-catenin signaling axis could be therapeutically targeted for the treatment of CRC invasion and metastasis. Citation Format: Shahanshah Khan, Hasan Zaki. NLRP12 suppresses colorectal cancer progression and invasion via downregulation of the Wnt/b-catenin pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2732.
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Abstract 2732: NLRP12 suppresses colorectal cancer progression and invasion via downregulation of the Wnt/b-catenin pathway
Tumor Biology, 2020Co-Authors: Shahanshah Khan, Hasan ZakiAbstract:Metastatic CRC is associated with increased mortality, underscoring the importance of understanding the molecular mechanism of CRC invasion and metastasis. We recently demonstrated that mice deficient in NLRP12, an innate immune sensor, are susceptible to CRC with increased incidence of invasive adenocarcinoma. Here, we investigated the molecular mechanism of NLRP12-mediated suppression of cancer progression and invasion using mouse models and in vitro biochemical studies. NLRP12−/− mice treated with azoxymethane plus dextran sodium sulfate developed higher tumor burden and invasive adenocarcinoma compared to WT mice. RNA-seq analysis showed significantly higher levels of protooncogenes, matrix metalloproteinases (Mmp 3, 7,8, 10, 12), and epithelial to mesenchymal transition (EMT) markers (Vim, Fn1, Foxc2, Zeb2, Ezh2) in NLRP12−/− tumors. To understand the underlying mechanism of increased expression of cancer promoting genes in NLRP12−/− tumors, we analyzed activation of various cell signaling pathways. To our surprise, there was no major difference in the activation NF-κB, ERK, JNK, and STAT3, which have previously been shown to be downregulated by NLRP12, between WT and NLRP12−/- tumors. However, we observed strikingly higher levels of β-catenin and expression of Wnt target genes (Ctnnb1, Axin2, Yap1, Tcf3, Lgr5, etc.) in NLRP12−/− tumors. Consistently, deletion of NLRP12 in APCmin/+ mice led to higher polyp development and activation of the Wnt/β-catenin pathway. Notably, hyperactivation of the Wnt/β-catenin pathway is a hallmark of CRC and about 80% of CRC patients carry mutations in the Wnt/β-catenin pathway. To further explore the link between NLRP12 and the Wnt/β-catenin pathway, we overexpressed NLRP12 in HEK293T cells and CRC cell line MC38. NLRP12-overexpressed cells showed reduced activation of β-catenin and expression of Wnt target genes following stimulation with Wnt3a. An opposite result was observed when NLRP12 was knocked out from these cell lines. Consistently, NLRP12-KO MC38 cells exhibited increased proliferation, colony formation, and migration. These data for the first time demonstrate that NLRP12 is an intrinsic negative regulator of the Wnt/β-catenin pathway. Overall, these findings reveal a novel CRC suppression pathway involving NLRP12 and suggest that the NLRP12/β-catenin signaling axis could be therapeutically targeted for the treatment of CRC invasion and metastasis. Citation Format: Shahanshah Khan, Hasan Zaki. NLRP12 suppresses colorectal cancer progression and invasion via downregulation of the Wnt/b-catenin pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2732.
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Crosstalk between NLRP12 and JNK during Hepatocellular Carcinoma.
International journal of molecular sciences, 2020Co-Authors: Shahanshah Khan, Hasan ZakiAbstract:Hepatocellular carcinoma (HCC), a leading cause of cancer-related death, is initiated and promoted by chronic inflammation. Inflammatory mediators are transcriptionally regulated by several inflammatory signaling pathways, including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). cJun N-terminal kinase (JNK), a member of the MAPK family, plays a central role in HCC pathogenesis. Pathogen-associated molecular patterns (PAMPs) activate JNK and other MAPK upon recognition by toll-like receptors (TLRs). Apart from TLRs, PAMPs are sensed by several other pattern recognition receptors, including cytosolic NOD-like receptors (NLRs). In a recent study, we demonstrated that the NLR member NLRP12 plays a critical role in suppressing HCC via negative regulation of the JNK pathway. This article briefly reviews the crosstalk between NLRP12 and JNK that occurs during HCC.
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NLRP12 suppresses hepatocellular carcinoma via downregulation of cJun N-terminal kinase activation in the hepatocyte
eLife, 2019Co-Authors: S. M. Nashir Udden, Youn-tae Kwak, Victoria Godfrey, Abdul Wadud Khan, Shahanshah Khan, Nicolas Loof, Lan Peng, Hao Zhu, Hasan ZakiAbstract:Hepatocellular carcinoma (HCC) is a deadly human cancer associated with chronic inflammation. The cytosolic pathogen sensor NLRP12 has emerged as a negative regulator of inflammation, but its role in HCC is unknown. Here we investigated the role of NLRP12 in HCC using mouse models of HCC induced by carcinogen diethylnitrosamine (DEN). NLRP12-/- mice were highly susceptible to DEN-induced HCC with increased inflammation, hepatocyte proliferation, and tumor burden. Consistently, NLRP12-/- tumors showed higher expression of proto-oncogenes cJun and cMyc and downregulation of tumor suppressor p21. Interestingly, antibiotics treatment dramatically diminished tumorigenesis in NLRP12-/- mouse livers. Signaling analyses demonstrated higher JNK activation in NLRP12-/- HCC and cultured hepatocytes during stimulation with microbial pattern molecules. JNK inhibition or NLRP12 overexpression reduced proliferative and inflammatory responses of NLRP12-/- hepatocytes. In summary, NLRP12 negatively regulates HCC pathogenesis via downregulation of JNK-dependent inflammation and proliferation of hepatocytes.
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The NLRP12 Sensor Negatively Regulates Autoinflammatory Disease by Modulating Interleukin-4 Production in T Cells
Immunity, 2015Co-Authors: John R. Lukens, Hasan Zaki, Peter Vogel, Prajwal Gurung, Patrick J. Shaw, Maggie J. Barr, Scott A. Brown, Hongbo Chi, Thirumala-devi KannegantiAbstract:SUMMARY Missense mutations in the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing family of gene 12 (NLRP12) are associated with periodic fever syndromes and atopic dermatitis in humans. Here, we have demonstrated a crucial role for NLRP12 in negatively regulating pathogenic T cell responses. NLRP12 / mice responded to antigen immunization with hyperinflammatory T cell responses. Furthermore, transfer of CD4 + CD45RB hi NLRP12 / T cells into immunodeficient mice led to more severe colitis and atopic dermatitis. NLRP12 deficiency did not, however, cause exacerbated ascending paralysis during experimental autoimmune encephalomyelitis (EAE); instead, NLRP12 / mice developed atypical neuroinflammatory symptoms that were characterized by ataxia and loss of balance. Enhanced T-cell-mediated interleukin-4 (IL-4) production promotes the development of atypical EAE disease in NLRP12 / mice. These results define an unexpected role for NLRP12 as an intrinsic negative regulator of T-cell-mediated immunity and identify altered NF-kB regulation and IL-4 production as key mediators of NLRP12-associated disease.