title: Myeloid cell expressed proprotein convertase FURIN attenuates inflammation.
abstract: The proprotein convertase enzyme FURIN processes immature pro-proteins into functional end- products. FURIN is upregulated in activated immune cells and it regulates T-cell dependent peripheral tolerance and the Th1/Th2 balance. FURIN also promotes the infectivity of pathogens by activating bacterial toxins and by processing viral proteins. Here, we evaluated the role of FURIN in LysM+ myeloid cells in vivo. Mice with a conditional deletion of FURIN in their myeloid cells (LysMCre-fur(fl/fl)) were healthy and showed unchanged proportions of neutrophils and macrophages. Instead, LysMCre-fur(fl/fl) mice had elevated serum IL-1β levels and reduced numbers of splenocytes. An LPS injection resulted in accelerated mortality, elevated serum pro-inflammatory cytokines and upregulated numbers of pro-inflammatory macrophages. A genome-wide gene expression analysis revealed the overexpression of several pro-inflammatory genes in resting FURIN-deficient macrophages. Moreover, FURIN inhibited Nos2 and promoted the expression of Arg1, which implies that FURIN regulates the M1/M2-type macrophage balance. FURIN was required for the normal production of the bioactive TGF-β1 cytokine, but it inhibited the maturation of the inflammation-provoking TACE and Caspase-1 enzymes. In conclusion, FURIN has an anti-inflammatory function in LysM+ myeloid cells in vivo.
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Zuzet Martinez
authors.initials: ZM
authors.lastname: Cordova
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Anna
authors.initials: A
authors.lastname: Grönholm
authors.affiliation: Computational Biology, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Kytölä
authors.affiliation: Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Food Microbiology and Bioprocessing, Università degli Studi di Milano, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Taverniti
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Hämäläinen
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Aittomäki
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Wilhelmiina
authors.initials: W
authors.lastname: Niininen
authors.affiliation: School of Medicine, University of Tampere, Tampere, Finland.|Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Junttila
authors.affiliation: Computational Biology, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Ylipää
authors.affiliation: Computational Biology, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nykter
authors.affiliation: Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland.|Department of Dermatology, Tampere University Hospital, Tampere, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
mesh_terms: D000072198:ADAM17 Protein / Q000378:metabolism; D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D045683:Furin / Q000502:physiology*; D005786:Gene Expression Regulation; D007249:Inflammation / Q000517:prevention & control*; D053583:Interleukin-1beta / Q000097:blood; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000201:enzymology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D053773:Transforming Growth Factor beta1; D045683:Furin; D020170:Caspase 1; D000072198:ADAM17 Protein
keywords: FURIN; Immune response; Immunity; Immunology and Microbiology Section; LysM; TGF-β1; cytokine; macrophage