sFgl2-Treg Positive Feedback Pathway Protects against Atherosclerosis

Soluble fibrinogen-like protein 2 (sFgl2), a novel effector of regulatory T cells (Tregs), has been demonstrated to have potent immunosuppressive functions. Multiple studies indicate that Tregs could exert important atheroprotective effects, but their numbers gradually decrease during atherogenesis. The receptor of sFgl2 can be expressed on Treg precursor cells, while the role of sFgl2 on Treg differentiation and atherosclerosis progression remains unclear. Firstly, we detected that the sFgl2 was decreased in humans and mice with atherosclerotic diseases and was especially lower in their vulnerable plaques. Then, we used both Adeno-associated virus-sFgl2 (AAV-sFgl2)-injected ApoE^-/- mice, which is systemic overexpression of sFgl2, and sFgl2^TgApoE^-/- bone marrow cells (BMC)-transplanted ApoE^-/- mice, which is almost immune-system-specific overexpression of sFgl2, to explore the role of sFgl2 in atherosclerosis. Our experiment data showed that AAV-sFgl2 and BMT-sFgl2 could reduce atherosclerotic area and enhance plaque stability. Mechanistically, sFgl2 increases the abundance and immunosuppressive function of Tregs, which is partly mediated by binding to FcγRIIB receptors and phosphorylating Smad2/3. Collectively, sFgl2 has an atheroprotective effect that is mainly achieved by forming a positive feedback pathway with Treg. sFgl2 and Treg could synergistically protect against atherosclerosis.