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Cytokine profile in a cohort of healthy blood donors carrying polymorphisms in genes encoding the nlrp3 inflammasome
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.ORCID iD: 0000-0002-9826-0462
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden.
Division of Rheumatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, SE-581 85 Linköping, Sweden.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: The 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 Methods: Genotyping 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 noncarrier controls.

Results & Discussion: The 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. These data suggest that these combined polymorphisms creates 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.

Keywords [en]
Auto-inflammation, Cytokines, Inflammasome, Interleukin-1β, Leukocytes
National Category
Medical and Health Sciences Immunology
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-32006OAI: oai:DiVA.org:oru-32006DiVA, id: diva2:656204
Available from: 2013-10-15 Created: 2013-10-14 Last updated: 2017-10-17Bibliographically approved
In thesis
1. Inflammasomes: defense guardians in host-microbe defence
Open this publication in new window or tab >>Inflammasomes: defense guardians in host-microbe defence
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The inflammasomes are emerging as key regulators of the innate immune response as they response to cellular infection, tissue damage and/or stress. Activated inflammasomes provide a signalling platform for caspase-1 activation which subsequently processes the maturation of interleukin (IL)-1β and IL-18, and in addition promotes cell death, named pyroptosis. These effector mechanisms of the inflammasome constitute an important part of the innate immune response in host-defence.

The aims of this thesis were to elucidate if the inflammasome is activated by specific pathogens, and if genetic variations lead to susceptibility to severe inflammatory diseases, such as blood stream infections. We found that the commensal pathogens Staphylococcus aureus and Propionibacterium acnes induce caspase-1 activation, the latter being a stronger activator. The data also propose that it is rather the bacterial ligands than the secreted toxins of P. acnes that induce inflammasome activation. Even though the S. aureus PVL-toxin induces a caspase-1 activation, involvement of other virulence factors are of importance. Upon S. aureus and P. acnes stimulation, inter-individual variations were found, implying that the characteristics of the host innate immune system, rather than the properties of the bacteria, are decisive for the inflammatory response. Indeed, healthy individuals with the combined polymorphisms of the NLRP3 inflammasome (C10X/Q705K) have higher levels of spontaneous IL-1β, and most intriguingly C10X polymorphism showed a strong correlation with patients with bacteremia.

In conclusion, these studies suggest that different pathogens activate the inflammasomes to various degrees. The genetics of the host innate immune system, rather than the properties of the bacteria, define the inflammatory response against these bacteria, and specific genetic variations such as C10X polymorphism can increase the susceptibility for disease development.

Place, publisher, year, edition, pages
Örebro: Örebro universitet, 2013. p. 76
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 88
Keywords
Innate immunity, inflammasome, leukocytes, cytokines, Staphylococcus aureus, Propionibacterium acnes, inflammation, infection, gene variants, polymorphism.
National Category
Medical and Health Sciences
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-28523 (URN)978-91-7668-923-3 (ISBN)
Public defence
2013-06-05, Wilandersalen, M-huset, Universitetetssjukhuset Örebro, Grev Rosen gatan 18, Örebro, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-04-02 Created: 2013-04-02 Last updated: 2017-10-17Bibliographically approved

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Sahdo, BerollaFransén, KarinIdosa, Berhane AsfawSöderquist, BoKelly, AnneSärndahl, Eva

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