Myeloid cell expressed proprotein convertase FURIN attenuates inflammation

// Zuzet Martinez Cordova 1 , Anna Gronholm 1 , Ville Kytola 2 , Valentina Taverniti 3 , Sanna Hamalainen 1 , Saara Aittomaki 1 , Wilhelmiina Niininen 1 , Ilkka Junttila 4,5 , Antti Ylipaa 2 , Matti Nykter 2 and Marko Pesu 1,6 1 Team Immunoregulation, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland 2 Team Computational Biology, Institute of Biosciences and Medical Technology (BioMediTech), University of Tampere, Tampere, Finland 3 Department of Food, Environmental and Nutritional Sciences (DeFENS), Division of Food Microbiology and Bioprocessing, Universita degli Studi di Milano, Milan, Italy 4 School of Medicine, University of Tampere, Tampere, Finland 5 Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland 6 Department of Dermatology, Tampere University Hospital, Tampere, Finland Correspondence to: Marko Pesu, email: // Keywords : cytokine, FURIN, LysM, macrophage, TGF-β1, Immunology and Microbiology Section, Immune response, Immunity Received : February 25, 2016 Accepted : July 22, 2016 Published : August 05, 2016 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 .