Cytokine Profile in a Cohort of Healthy Blood Donors Carrying Polymorphisms in Genes Encoding the NLRP3 Inflammasome

Abstract

BackgroundThe NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.Materials and MethodsGenotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.Results & DiscussionThe prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1β as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.

Genetic Variants of the NLRP3 Inflammasome Are Associated with Stroke in Patients with Rheumatoid Arthritis

“…Genotype frequencies were in Hardy-Weinberg equilibrium for both SNP (p > 0.1), and comparable with previous findings from Swedish datasets 8,9,14 . Table 1 shows demographic and clinical characteristics of the patients.…”

“…The CARD8-C10X polymorphism (rs2043211), which introduces an early stop codon, has been shown to impair the NF-κB-inhibiting properties of the protein 17 , but functional studies in relation to inflammasomes are lacking. A number of reports have described interacting effects between NLRP3-Q705K and CARD8-C10X, for example, regarding RA 8 , aortic abdominal aneurysms 18 , inflammatory bowel disease 19,20 , and plasma levels of IL-1β in healthy individuals 14 .…”

NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta‐analysis

“…Healthy blood donors carrying combined Q705K+C10X polymorphisms were reported to show higher plasma levels of IL‐1β and IL‐33 . The interaction of Q705K and C10X polymorphisms was reported to confer an effect on inflammatory bowel disease (IBD) and abdominal aortic aneurysms (AAA) .…”

“…Combined analysis of multiple SNPs can help to reveal the potential genetic susceptibility that cannot be explained using one single SNP. Combined polymorphisms (Q705K polymorphism in NLRP3 gene combined with C10X polymorphism in CARD8 gene) have been reported to create inflammasomes with increased basal activation state, which provide a more favorable innate immune response . Just the same combined polymorphisms have been reported to confer susceptibility to Crohn's disease in Swedish men .…”

The Association of <b><i>CARD8</i></b> rs2043211 Polymorphism with Preeclampsia in the Chinese Han Population

“…The deficiency of apoptosis may induce maternal immune response toward the fetus, while excessive apoptosis may result in placental ischemia and systemic endothelial damage [34]. As a functional variant in CARD8, polymorphism of rs2043211 yields a truncated non-functional protein, resulting in the loss of CARD8-mediated inhibition of caspase-1 and apoptosis [35], which may influence the onset of PE. Several recent studies have indicated associations between the polymorphism of rs2043211 with different inflammatory diseases, including inflammatory bowel disease and rheumatoid arthritis [16,17,18].…”