The Q705K Polymorphism in NLRP3 Is a Gain-of-Function Alteration Leading to Excessive Interleukin-1β and IL-18 Production

Verma, Deepti; Särndahl, Eva; Andersson, Henrik; Eriksson, Per; Fredrikson, Mats; Jönsson, Jan‐Ingvar; Lerm, Maria; Söderkvist, Peter

doi:10.1371/journal.pone.0034977

Cited by 135 publications

(119 citation statements)

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“…The association of the Q705K polymorphism with upregulated CRP levels in unaffected males suggests that the polymorphism may impart an inflammasome-mediated inflammatoty phenotype to males. The polymorphism Q705K in the NLRP3 gene is a gain-of-function polymorphism responsible for the abnormal production of IL-1β leading to the deleterious effect of inflammation (18). During inflammation, IL-1β induced the expression of CRP, suggesting a link between the inflammasome and minor allele of the Q705K polymorphism and CRP present in males (27).…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies have also revealed the association of the Q705K polymorphism in the NLRP3 gene (rs35829419) with various inflammatory diseases including celiac disease (9), diabetes type-1 (8), abdominal aortic aneurysms (14), Crohn's disease (15) and rheumatoid arthritis (10 CARD8 (C10X) genes was found to be associated with rheumatoid arthritis (10) and Crohn's disease (15,16). Considering a possible key role of the NLRP3 inflammasome in promoting myocardial inflammation (17) and athero sclerosis through the production of pro-inflammatory cytokine IL-1β (18), the aim of the present study was to investigate the effect of Q705K polymorphism in NLRP3 gene and the risk of developing MI in a northern Swedish population.…”

Section: Introductionmentioning

confidence: 99%

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Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

et al. 2013

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Abstract. Inflammation is a multifaceted process that underlies the pathophysiology of acute myocardial infarction (MI). Variations in the inflammasome-related NLRP3 gene have been associated with risk for a number of different inflammatory diseases. Therefore, Q705K polymorphism in NLRP3 gene likely confers susceptibility to risk for MI. A First-ever myocardial Infarction study in Ac-county (FIA) cohort comprising 555 MI patients and 1,016 controls was used to genotype rs35829419 in the NLRP3 gene by TaqMan single-nucleotide polymorphism assay. C-reactive protein (CRP) was measured in the study participants by ELISA. The results showed no significant association between the variant rs35829419 and MI. However, the minor A allele of the rs35829419 polymorphism conferred a protective effect against the risk of developing MI in females. The minor A allele of rs35829419 polymorphism was also associated with increased CRP levels in males. Results of the study suggested a gender-specific deregulation of NLRP3 gene mediated by rs35829419 polymorphism that confers protection against MI in females but has no effect on MI susceptibility in males. However, the rs35829419 polymorphism was associated with increased CRP levels among the male subjects, thereby demonstrating the possible effect of the Q705K polymorphism in elevating the basal active state of innate immune response. IntroductionCoronary artery disease, including myocardial infarction (MI), is known to be a leading cause of mortality worldwide. The individual's genetic constitution as well as environmental factors are crucial in the pathological progression of the disease (1). Among the known etiological factors, inflammation is a major contributor for the progression of atherosclerosis and the subsequent rupture of the unstable plaque, resulting in MI (2). Defense mechanisms against inflammation serve as a defense tool of innate immune response against both exogenous pathogens and endogenous sterile injury. However, the uncontrolled inflammatory response often suppresses the repair mechanism, thereby leading to the clinical manifestation of the inflammatory disease characterized by elevated levels of inflammatory markers, such as interleukin (IL)-1β, IL-18, interferon γ, tumor necrosis factor-α and C-reactive protein (CRP). The recent finding regarding the NLRP3-induced production of the proinflammatory cytokine IL-1β in individuals with a mutation in the NLRP3 gene has placed much focus on the NLRP3 inflammasome (3,4). The NLRP3 inflammasome, an intracellular macromolecular complex, which consists of the NLRP3 scaffold, the adaptor protein apoptosis speck-like protein contaning CARD and caspase-1, processes the immature proinflammatory cytokine IL-1β to its active form and renders the recognition of pathogen and danger-derived molecules in the cytosol (5).Genetic variants in the genes encoding for proteins of the NLRP3 inflammasome have been studied in association with various inflammatory diseases (6-11). Germline alterations in the NLRP3 gene encoding the NLR...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

et al. 2013

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“…Several allelic variants of genes encoding danger receptors or molecules associated with signalling pathways from these receptors have been described. [78][79][80] Although complete deficiency of these molecules strongly compromises immune response, these are generally rare events. By contrast, genes for TLRs are highly polymorphic and encode many variants with either higher or lower activity in terms of ligand binding or signal transduction.…”

Section: Future Perspectives On Plasticity and Regulation Of Danger Smentioning

confidence: 99%

Danger signalling during cancer cell death: origins, plasticity and regulation

et al. 2013

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Accumulating data indicates that following anti-cancer treatments, cancer cell death can be perceived as immunogenic or tolerogenic by the immune system. The former is made possible due to the ability of certain anti-cancer modalities to induce immunogenic cell death (ICD) that is associated with the emission of damage-associated molecular patterns (DAMPs), which assist in unlocking a sequence of events leading to the development of anti-tumour immunity. In response to ICD inducers, activation of endoplasmic reticulum (ER) stress has been identified to be indispensable to confer the immunogenic character of cancer cell death, due to its ability to coordinate the danger signalling pathways responsible for the trafficking of vital DAMPs and subsequent anti-cancer immune responses. However, in recent times, certain processes apart from ER stress have emerged (e.g., autophagy and possibly viral response-like signature), which have the ability to influence danger signalling. In this review, we discuss the molecular nature, emerging plasticity in the danger signalling mechanisms and immunological impact of known DAMPs in the context of immunogenic cancer cell death. We also discuss key effector mechanisms modulating the interface between dying cancer cells and the immune cells, which we believe are crucial for the therapeutic relevance of ICD in the context of human cancers, and also discuss the influence of experimental conditions and animal models on these. The ultimate outcome of an immune response to cancer cell death (i.e., anti-tumourigenic, pro-tumourigenic or autoimmunity or different combinations of these) tends to be complex and may depend on a number of factors like the type of the cancer cells that die and their in vivo location, the type of cell death pathway they follow to die, the types of immune cells that phagocytose them or interact with them and, last but not the least, whether a cancer antigen is recognized or not. Tolerogenicity towards cell death, as happens predominantly when cancer cells undergo physiological apoptosis (after treatment with most anti-cancer therapies), depends on a number of factors including the presence of immunosuppressive factors, absence or inactivation of DAMPs, induction of tolerogenic dendritic cells (DCs), 'suboptimal' activation of CD8 þ T cells only and apoptotic 'mimicry'.Accentuated immunogenicity exhibited by cancer cells undergoing immunogenic cell death (ICD; after treatment with selected anti-cancer therapies), depends on a number of factors like emission of DAMPs (i.e., surface exposure of certain chaperones, secretion or release of certain nucleotides and endokines), presence of immunostimulatory factors, induction of DC maturation (both phenotypic and functional) and optimal activation of CD4 þ ab, CD8 þ ab and gd T-cell responses. Certain DAMPs are actively trafficked during ICD by danger signalling pathways, which are instigated and regulated by a complex interplay between endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) production and cert...

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“…However, as in many genetic disorders, environmental factors are also effective in the phenotype of the disease, in addition to genetic factors (16)(17)(18)(19)(20). A Swedish study reported increased activity of the CIAS1-Q705K polymorphism as demonstrated by the increased spontaneous and stimulated release of IL-1 beta and IL-18, which are responsible in chronic inflammatory diseases (21). In our study, Q705K polymorphism was detected in 4 patients and 3 individuals in the study and control groups, respectively.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of autoinflammatory disease genes in nasal polyposis*

Köseoğlu¹,

Özcan²,

İkincioğulları³

et al. 2015

Turk J Med Sci

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Background/aim: To investigate cold-induced autoinflammatory syndrome 1 (CIAS1) gene polymorphisms that cause autoinflammatory diseases in patients with nasal polyposis (NP). Materials and methods:The study included 30 patients diagnosed with NP and 30 healthy age-matched individuals as a control group. CIAS1 polymorphisms were assessed by DNA sequence analysis. Patients with nasal polyps and the control group were compared in terms of gene polymorphisms. Each of the 8 polymorphisms of the CIAS1 gene was analyzed separately in the patient group. Results:The most frequently observed polymorphisms in the patient group were c.732G > A in 83%, c.663C > T in 23%, and c.1308C > A in 23% of the patients. c.732G > A polymorphism was evaluated separately. Guanine was transformed to adenine at the 732nd nucleotide position of the CIAS1 gene in the cDNA of chromosome 1. Conclusion:The CIAS1 gene c.732G > A polymorphism was thought to be responsible for an increase in disease susceptibility. The frequency of the "A" allele is higher in the patient group compared to the control group. Autoinflammatory diseases seem like a candidate to be one of these factors. This is the first report to define the role of autoinflammatory diseases among these factors.

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The Q705K Polymorphism in NLRP3 Is a Gain-of-Function Alteration Leading to Excessive Interleukin-1β and IL-18 Production

Cited by 135 publications

References 50 publications

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

Danger signalling during cancer cell death: origins, plasticity and regulation

Evaluation of autoinflammatory disease genes in nasal polyposis*

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