Oncotarget

Research Papers: Immunology:

Myeloid cell expressed proprotein convertase FURIN attenuates inflammation

Zuzet Martinez Cordova, Anna Grönholm, Ville Kytölä, Valentina Taverniti, Sanna Hämäläinen, Saara Aittomäki, Wilhelmiina Niininen, Ilkka Junttila, Antti Ylipää, Matti Nykter and Marko Pesu _

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Oncotarget. 2016; 7:54392-54404. https://doi.org/10.18632/oncotarget.11106

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Abstract

Zuzet Martinez Cordova1, Anna Grönholm1, Ville Kytölä2, Valentina Taverniti3, Sanna Hämäläinen1, Saara Aittomäki1, Wilhelmiina Niininen1, Ilkka Junttila4,5, Antti Ylipää2, Matti Nykter2 and Marko Pesu1,6

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, Università 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.


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