Syndecan-3 positively regulates the pro-inflammatory function of macrophages
The tumour microenvironment (TME) is a highly structured ecosystem that surrounds a tumour and plays a crucial role in tumorigenesis. As one of the most abundant cell types in the TME, tumour-associated-macrophages (TAMs) can promote disease progression and resistance to therapy. Syndecan-3 (SDC3) is a cell-surface heparan sulphate proteoglycan expressed by TAMs, although its functional relevance in these cells remains unknown. Here, we demonstrated that proinflammatory cytokines drive the expression of SDC3 on the cell surface of macrophages. Genetic ablation of SDC3 in macrophages led to aberrant proliferation, adhesion and expression of CD40 and CD86 surface markers. Moreover, SDC3 defective macrophages exhibited distinctive gene expression patterns, leading to impaired tumour cell phagocytosis and increased tumour cell proliferation. Mechanistically, a decrease in the secretion of pro-inflammatory cytokines was observed in SDC3 KO macrophages, concomitant with impaired T cell effector functions. Additionally, a higher angiogenic capacity was observed in endothelial cells when co-cultured with macrophages deficient for SDC3, possibly mediated through an increased release of VEGFA, PECAM-1 and IL-8 by SDC3 KO cells. Collectively, we have identified SDC3 as a modulator of macrophage functions aiming at supporting a pro-inflammatory and anti-tumour phenotype in these cells. Overall design: To investigate the effect of Syndecan-3 in the regulation of macrophage pro-inflammatory functions, we established THP-1 cell lines in which Syndecan-3 has been knocked-out by CRISPR/Cas9. We then performed gene expression profiling analysis using data obtained from RNA-seq of two different cells in response to two different conditions. Comparative  gene expression profiling analysis of RNA-seq data for IFN-gamma-treated SDC3 KO and WT THP-1 cells.