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Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity.


ABSTRACT:

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.

Methods and 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.

SUBMITTER: Kappert K 

PROVIDER: S-EPMC3735592 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Proprotein convertase subtilisin/kexin type 3 promotes adipose tissue-driven macrophage chemotaxis and is increased in obesity.

Kappert Kai K   Meyborg Heike H   Fritzsche Jan J   Urban Daniel D   Krüger Janine J   Wellnhofer Ernst E   Kintscher Ulrich U   Fleck Eckart E   Stawowy Philipp P  

PloS one 20130806 8


<h4>Background</h4>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-associa  ...[more]

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