Abstract
BackgroundMatrix 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 ResultsMonocyte → 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/m2) had higher furin, MT1-MMP, and resistin gene expression compared to normal weight individuals (BMI<25kg/m2) 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.ConclusionsAcquisition 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.
Highlights
Chronic inflammation of adipose tissue is a key process in the development and progression of insulin resistance and atherosclerosis, significantly contributing to obesity-associated increases in cardiovascular mobidity and mortality [1,2]
The imbalance in the furin/serpinB8 ratio was confirmed using qRTPCR, demonstrating significant increases of furin mRNA in macrophages compared to monocytes, with serpinB8 transcripts only slightly decreasing in macrophages (Figure 1B)
Upregulation of furin, resulting in increased furinlike PCSK activity. This leads to furin-dependent activation of pro-MT1-Matrix metalloproteinase (MMP), which is crucial for obese white adipose tissue (WAT)-driven macrophage chemotaxis
Summary
Chronic inflammation of adipose tissue is a key process in the development and progression of insulin resistance and atherosclerosis, significantly contributing to obesity-associated increases in cardiovascular mobidity and mortality [1,2]. Elevated levels of cytokines/adipokines are released, further facilitating the inflammatory process [3] This cardiometabolic syndrome-associated tissue inflammation/remodeling typically requires the expression of matrix metalloproteinases (MMPs) [4], present with their counterpart TIMPs (tissue inhibitors of matrix metalloproteinases) in WAT of obese animal models [5]. Whereas furinspecific siRNA significantly inhibited MT1-MMP activity in macrophages, a PCSK-inhibitor completely abrogated proMT1-MMP activation, supporting the notion that both furin and PCSK5 target pro-MT1-MMP along its maturation pathway [10] Based on their overlap in expression and substrate specificity, these two PCSKs are commonly regarded as “furinlike” PCSKs [11]. The regulation and function of the natural furin-inhibitor serpinB8 and furin/MT1-MMP-activity in obesity-related tissue inflammation/remodeling is unknown. Dissecting the regulation of furin and its inhibitor serpinB8 should facilitate targeting inflammation/remodeling in cardiometabolic diseases
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