title: Increased inflammasome related gene expression profile in PBMC may facilitate T helper 17 cell induction in multiple sclerosis.
abstract: The NLRP3 inflammasome is a macromolecular complex importantly involved in IL-1β processing. A role for this has been described in multiple sclerosis (MS). One mechanism by which IL-1β might be involved in MS is by inducing pathogenic Th17 cells, i.e. GM-CSF+ Th17 cells. In the present study, we show that expression of the inflammasome related genes, NLRP3, caspase-1, IL-1β and the IL-1β/IL-1Ra ratio, was increased in PBMC from MS patients compared to healthy controls (HC). However, in an in vitro inflammasome activity assay with PBMC, IL-1β protein secretion and the IL-1β/IL-1Ra protein ratio were similar in MS patients and HC. Th cells cultured in the presence of supernatant derived from LPS/ATP inflammasome activated PBMC showed increased Th17 and GM-CSF+ Th17 cell frequencies in HC and MS patients and decreased anti-inflammatory IL-10+Th cell frequency in HC compared to Th cells cultured in the presence of control supernatant. Moreover, addition of the immune modulator calcitriol to the former condition resulted in reduced frequencies of Th17 and GM-CSF+Th17 cells, and also of IL-10+ Th cells. Evidently, our data indicate that inflammasome activity can skew the Th cell population toward a more pro-inflammatory composition, an effect that might be inhibited by vitamin D, and that might be importantly involved in inflammation within the central nervous system.
authors.affiliation: School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands
authors.forename: E
authors.initials: E
authors.lastname: Peelen
authors.forename: J
authors.initials: J
authors.lastname: Damoiseaux
authors.forename: A-H
authors.initials: AH
authors.lastname: Muris
authors.forename: S
authors.initials: S
authors.lastname: Knippenberg
authors.forename: J
authors.initials: J
authors.lastname: Smolders
authors.forename: R
authors.initials: R
authors.lastname: Hupperts
authors.forename: M
authors.initials: M
authors.lastname: Thewissen
mesh_terms: D000255:Adenosine Triphosphate / Q000494:pharmacology; D000328:Adult; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D058847:Inflammasomes / Q000235:genetics* / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053583:Interleukin-1beta / Q000097:blood / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014807:Vitamin D / Q000494:pharmacology; D055815:Young Adult
chemical_list: D058847:Inflammasomes; D053590:Interleukin 1 Receptor Antagonist Protein; D020381:Interleukin-17; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016753:Interleukin-10; D014807:Vitamin D; D000255:Adenosine Triphosphate