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AB0211 NEUTROPHIL-DERIVED EXOSOME S100A8/A9 INHIBITS ANGIOGENESIS IN SYSTEMIC SCLEROSIS

Background Systemic sclerosis (SSc) is an autoimmune disease characterized by vasculopathy, inflammation, and extensive fibrosis of the skin and organs. Exosomes (EXOs) are cell-derived vesicles 30-150 nm in size that contain various mRNAs, microRNAs and proteins. Objectives Here, we aimed to investigate the roles of EXOs in SSc pathogenesis, especially in angiogenesis. Methods EXOs were respectively isolated from plasma, cultured peripheral blood mononuclear cells (PBMCs) and neutrophil supernatants, and were identified by transmission electron microscopy. The expression of S100A8/A9 was measured by real-time PCR and ELISA. Proliferation, migration and scratch assays in human dermal microvascular endothelial cells (HDMECs) were used to study the influence of neutrophil EXOs and neutrophil EXOs S100A8/A9. We also performed a genome-wide transcriptome analysis on PBMCs from 19 SSc patients and 18 matched normal controls (NC) using Illumina BeadChip arrays. The ingenuity pathway analysis (IPA) tool and Database for Annotation, Visualization and Integrated Discovery (DAVID) were used for bioinformatics analysis. Results Plasma EXOs and neutrophil EXOs from SSc patients suppressed the proliferation and migration of HDMECs. Using a microarray analysis we found 28% genes upregulated in PBMCs could exist in EXOs, especially the S100 protein family, including S100A8/A9. High levels of S100A8/A9 were consistently verified in SSc plasma, PBMCs, plasma EXOs, PBMC EXOs and neutrophil EXOs. Particularly, S100A8/A9 expression in neutrophil EXOs was distinctly higher than that in PBMC EXOs in SSc patients. Furthermore, we found that neutrophil EXOs S100A8/A9 inhibit the proliferation and migration of HDMECs, and that might through Toll-like receptor 4 (TLR4) pathway. Conclusion S100A8/A9 is one of components of neutrophil EXOs that regulates vascular endothelial cell angiogenesis in SSc patients, most likely by activating the TLR4 signalling pathway. Acknowledgement This study was funded by grants from the National Key Research and Development Program of China (2016YFC0903900), National Natural Science Foundation of China (81671622), Hunan Provincial Natural Science Foundation (2018JJ3823), Clinical Research Fund of Xiangya Hospital Central South University (2014L10) and Independent Innovation Projects of Central South University (2018zzst290). Disclosure of Interests None declared