Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity.
BACKGROUND
Matrix metalloproteinase (MMP)-dependent extracellular matrix (ECM) remodeling is a key feature in cardiometabolic syndrome-associated adipogenesis and atherosclerosis. Activation of membrane-tethered (MT) 1-MMP depends on furin (PCSK3). However, the regulation and function of the natural furin-inhibitor serpinB8 and thus furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Here we aimed to determine the role of serpinB8/furin in obesity-associated chronic inflammation.


RESULTS
Monocyte → macrophage transformation was characterized by decreases in serpinB8 and increases in furin/MT1-MMP. Rescue of serpinB8 by protein overexpression inhibited furin-dependent pro-MT1-MMP activation in macrophages, supporting its role as a furin-inhibitor. Obese white adipose tissue-facilitated macrophage migration was inhibited by furin- and MMP-inhibition, stressing the importance of the furin-MMP axis in fat tissue inflammation/remodeling. Monocytes from obese patients (body mass index (BMI) >30kg/m(2)) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI<25kg/m(2)) with significant correlations of BMI/furin and furin/MT1-MMP. In vitro, the adipocytokine resistin induced furin and MT1-MMP in mononuclear cells (MNCs), while MCP-1 had no effect.


CONCLUSIONS
Acquisition of the inflammatory macrophage phenotype is characterized by an imbalance in serpinB8/furin, leading to MT1-MMP activation, thereby enhancing migration. Increases in MT1-MMP and furin are present in MNCs from obese patients. Dissecting the regulation of furin and its inhibitor serpinB8 should facilitate targeting inflammation/remodeling in cardiometabolic diseases.
Department of Medicine/Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany.
Kai
K
Kappert
Heike
H
Meyborg
Jan
J
Fritzsche
Daniel
D
Urban
Janine
J
Krüger
Ernst
E
Wellnhofer
Ulrich
U
Kintscher
Eckart
E
Fleck
Philipp
P
Stawowy
D000273:Adipose Tissue / Q000473:pathology*; D000818:Animals; D002460:Cell Line; D002633:Chemotaxis; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D045683:Furin / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000150:complications; D008264:Macrophages / Q000473:pathology*; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009000:Monocytes / Q000473:pathology; D009765:Obesity / Q000150:complications / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D052243:Resistin / Q000378:metabolism; D015843:Serpins / Q000378:metabolism
D004792:Enzyme Precursors; D052243:Resistin; C108403:SERPINB8 protein, human; D015843:Serpins; C468731:FURIN protein, human; D045683:Furin; D053511:Matrix Metalloproteinase 14