Syndecan-3 positively regulates the pro-inflammatory function of macrophages

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• The tumour microenvironment (TME) is critical for cancer development.
• Tumour-associated macrophages (TAMs) are key players in the TME, often promoting tumour progression.
• The function of Syndecan-3 (SDC3) in TAMs is currently unknown.

Purpose of the Study:

• To investigate the functional role of Syndecan-3 (SDC3) in macrophages within the tumour microenvironment.
• To elucidate the mechanisms by which SDC3 influences macrophage phenotype and anti-tumour activity.

Main Methods:

• Studied SDC3 expression in macrophages induced by pro-inflammatory cytokines.
• Utilized genetic ablation of SDC3 in macrophages (SDC3 KO).
• Analyzed macrophage proliferation, adhesion, surface marker expression (CD40, CD86), gene expression, and cytokine secretion.
• Assessed the impact of SDC3-deficient macrophages on tumour cell phagocytosis, proliferation, T cell effector functions, and angiogenesis.

Main Results:

• Pro-inflammatory cytokines increase SDC3 expression on macrophages.
• SDC3 deficiency in macrophages resulted in altered proliferation, adhesion, and CD40/CD86 expression.
• SDC3-deficient macrophages showed impaired tumour cell phagocytosis and promoted tumour cell proliferation.
• Macrophages lacking SDC3 exhibited reduced pro-inflammatory cytokine secretion, impairing T cell function.
• Endothelial cells co-cultured with SDC3-deficient macrophages showed increased angiogenic capacity, potentially via VEGFA, PECAM-1, and IL-8 release.

Conclusions:

• SDC3 modulates macrophage functions to support a pro-inflammatory and anti-tumourigenic phenotype.
• Targeting SDC3 in TAMs could be a potential therapeutic strategy to enhance anti-tumour immunity.