AGE/HMGB1-RAGE axis in systemic sclerosis

Groendijk, Iris (2018) AGE/HMGB1-RAGE axis in systemic sclerosis. Master's Research Project 1, Biomedical Sciences.

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Abstract

Introduction. Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive fibrosis of the skin and internal organs, widespread vasculopathy, and autoantibodies against several cellular antigens. An unique feature of SSc is that autoimmunity and vasculopathy precede fibrosis. Microvascular injury results in generation of reactive oxygen species (ROS), which via transforming growth factor-β1 (TGF-β1) causes fibroblast to myofibroblast differentiation and extracellular matrix (ECM) components formation, causing fibrosis in skin and internal organs. Advanced glycation end products (AGEs) are a heterogeneous group of molecules formed under influence of ROS and bind to the receptor for AGEs (RAGE). Also High Mobility Group Box 1 (HMGB1) can bind to RAGE leading to proinflammatory responses. The aim of this study is to investigate the role of the HMGB1/AGE-RAGE axis in the pathogenesis of SSc. Materials & Methods. Skin biopsies of SSc patients with affected and unaffected skin were stained immunohistochemically for HMGB1, RAGE, AGEs (CML, pentosidine, and MG-H1), and interferon (IFN) type 1 induced protein MxA. Furthermore healthy human dermal fibroblasts (HDFs) were cultured and stimulated with AGE-BSA, HMGB1, and TGF-β1. mRNA levels were measured with RT-qPCR of several parameters including myofibroblast marker α-smooth muscle actin (α-SMA). Results. MG-H1 expression in SSc skin biopsies is upregulated in both affected and unaffected SSc skin compared to healthy control skin. The other AGEs, HMGB1, and RAGE did not show a clear expression in the SSc skin biopsies. MxA was solely expressed in the epidermis and endothelial cells of SSc skin compared to healthy control skin. After 24 hours of HDF stimulation with different compounds, no difference in α-SMA mRNA expression levels were observed. Interferon induced IFI44L and inflammation related IL-6 were both significantly increased after stimulation with AGE-BSA. Conclusion. MG-H1 proteins are upregulated in both affected and unaffected SSc skin, indicating it has a role in the pathogenesis of SSc. AGE-BSA stimulation in healthy HDFs did not result in fibrosis, but an inflammatory milieu was created, suggesting a pre-fibrotic stadium.

Item Type:	Thesis (Master's Research Project 1)
Supervisor name:	Westra, J.
Degree programme:	Biomedical Sciences
Thesis type:	Master's Research Project 1
Language:	English
Date Deposited:	01 Oct 2018
Last Modified:	02 Nov 2018 13:48
URI:	https://fse.studenttheses.ub.rug.nl/id/eprint/18659

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