Siglec-10/G抑制STAT6通路导致巨噬细胞M1型极化和吞噬功能下降促进动脉粥样硬化斑块不稳定的机制研究

巨噬细胞M1型极化和吞噬功能下降是导致动脉粥样硬化（AS）斑块不稳定的重要原因。前期我们通过对人体颅内动脉标本的分析发现唾液酸结合免疫球蛋白样凝集素-10（Siglec-10）更多出现在进展型AS斑块中；通过细胞实验发现Siglec-10/G可使巨噬细胞向M1型极化和吞噬功能下降，且STAT6的磷酸化激活减少。基于前期实验证据我们推测：在AS病理状态下，Siglec-10/G可能通过抑制STAT6信号通路，使巨噬细胞向M1型极化和吞噬功能下降，进而影响斑块的稳定性。我们拟通过：临床研究探索颅内AS患者外周血Siglec-10表达水平与斑块稳定性的关系；运用Siglec-G和ApoE双基因敲除小鼠构建AS动物模型，结合细胞模型探索Siglec-G对巨噬细胞极化和功能的影响，并验证Siglec-G是否通过调控STAT6通路从而影响巨噬细胞的功能。本研究力求为AS的治疗提供新的靶点和理论基础。

Accumulating evidences suggest the pivotal role of M1 macrophage polarization and phagocytic dysfunction in the development of unstable atherosclerotic plaques. Our preliminary data from human intracranial artery specimens suggested that sialic acid-binding immunoglobulin-like lectins (Siglec-10) presented more in progressive atherosclerotic plaques. In previous cell experiments, we found that Siglec-10/G mediated M1 macrophage polarization and phagocytic dysfunction, accompanying with suppression of STAT6 phosphorylation. From our previous experiments, we speculated that, Siglec-10/G might urge macrophages polarization towards M1 subtype and aggravate phagocytic dysfunction through inhibiting the STAT6 signaling pathway, thereby affecting the stability of atherosclerotic plaques. We propose to conduct the clinical study to explore the relationship between the expression of Siglec-10 in the peripheral blood and the stability of plaques among intracranial atherosclerosis patients. We plan to construct the atherosclerosis animal model by using Siglec-G and ApoE double gene knockout mice. We propose to combine the atherosclerosis animal model with the cell model to study the effect of Siglec-G on the polarization and phagocytic function of macrophages, as well as to clarify whether Siglec-G mediates the function of macrophages by regulating the STAT6 signaling pathway. The current study aims at providing new targets and theoretical evidences for therapeutics of atherosclerosis.