title: MicroRNA-941 Expression in Polymorphonuclear Granulocytes Is Not Related to Granulomatosis with Polyangiitis.
abstract: Jumonji Domain-Containing Protein 3 (JMJD3)/lysine demethylase 6B (KDM6B) is an epigenetic modulator that removes repressive histone marks on genes. Expression of KDM6B mRNA is elevated in leukocytes from patients with ANCA-associated vasculitis (AAV) and has been suggested to be the reason for higher proteinase 3 (PR3) mRNA expression in these cells due to derepression of PRTN3 gene transcription. MicroRNA-941 (miR-941) has been shown to target KDM6B mRNA and inhibit JMJD3 production. We therefore investigated whether polymorphonuclear granulocytes (PMNs) from patients suffering from granulomatosis with polyangiitis (GPA) have lower expression of miR-941 than healthy control donors as a biological cause for higher JMJD3 levels. We found no significant difference in the degree of maturation of PMNs from GPA patients (n = 8) and healthy controls (n = 11) as determined from cell surface expression of the neutrophil maturation marker CD16 and gene expression profile of FCGR3B. The expression of PRTN3 and KDM6B mRNAs and miR-941 was not significantly different in GPA patients and healthy controls. Transfection of pre-miR-941 into the neutrophil promyelocyte cell line PLB-985 cells did not result in reduction of the KDM6B mRNA level as shown previously in a hepatocellular carcinoma cell line. The amount of PR3 in PMNs from GPA patients and healthy controls was comparable. In conclusion, we found that PRTN3 mRNA, KDM6B mRNA, and miR-941 expression levels in PMNs do not differ between GPA patients and healthy controls, and that miR-941 does not uniformly regulate KDM6B mRNA levels by inducing degradation of the transcript. Thus, decreased miR-941 expression in PMNs cannot be part of the pathogenesis of GPA.
authors.affiliation: The Granulocyte Research Laboratory, Department of Hematology, National University Hospital, Copenhagen, Denmark.
authors.forename: Jesper Brink
authors.initials: JB
authors.lastname: Svendsen
authors.affiliation: Department of Rheumatology, National University Hospital, Copenhagen, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Baslund
authors.affiliation: The Granulocyte Research Laboratory, Department of Hematology, National University Hospital, Copenhagen, Denmark.
authors.forename: Elisabeth Præstekjær
authors.initials: EP
authors.lastname: Cramer
authors.affiliation: The Finsen Laboratory, National University Hospital, Copenhagen, Denmark.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Rapin
authors.affiliation: The Granulocyte Research Laboratory, Department of Hematology, National University Hospital, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.affiliation: The Granulocyte Research Laboratory, Department of Hematology, National University Hospital, Copenhagen, Denmark.
authors.forename: Jack Bernard
authors.identifier: http://orcid.org/0000-0002-7429-5388
authors.initials: JB
authors.lastname: Cowland
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D016022:Case-Control Studies; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D053146:Myeloblastin / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism*; D025341:Principal Component Analysis; D012333:RNA, Messenger / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D055815:Young Adult
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; D017452:Receptors, IgG; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D053146:Myeloblastin