CCL17/CCR4调控ERK/AP1/SRA信号通路促进小胶细胞极化参与脑出血后血肿清除的机制研究

脑出血(ICH)后血肿及其溶解产物是影响患者预后的重要因素。选择性激活M2型小胶质细胞吞噬血肿，在ICH治疗中极具前景。我们前期发现激活CCR4促进M2型小胶质细胞活化，促进血肿清除，但其机制尚不明确。我们的预实验发现：给予CCR4特异性配体CCL17能增加M2型小胶质细胞，并促进清道夫受体SRA的表达。鉴于文献证实SRA能清除氧化的血红蛋白等，我们推测CCL17/CCR4通过ERK/AP1/SRA通路调控小胶质细胞极化介导ICH后血肿清除。本项目拟通过小鼠ICH模型和原代小胶质细胞离体出血共培养模型，运用11.0T MRI影像技术，结合免疫共沉淀、流式细胞仪、免疫荧光吞噬血肿等手段，从分子、细胞和动物多个层面，明确CCL17/CCR4对小胶质细胞极化调控、血肿清除的作用及分子机制；从而证实CCL17/CCR4通过ERK/AP1/SRA通路调控小胶质细胞介导血肿清除，为ICH治疗提供新靶点

Hematoma and its dissolution products are important factors affecting the prognosis of after intracerebral hemorrhage (ICH) patients. Selective activation of M2 microglia to phagocyte hematomas is a potential treatment for ICH. We previously found that CCR4 activation activate microglia to M2, promoted hematoma clearance, and had a neuroprotective effect on ICH, but the mechanism remains unclear. We found that ERK, AP1 and SRA elevated after ICH. Treatment with recombinant CCL17 increased the number of M2 microglia and significantly decreased the number of M1 microglia. Based on those studies, we proposed a scientific hypothesis: CCR4 regulates microglia polarization mediated hematoma removal after ICH through the ERK/AP1/SRA pathway. We will use mice ICH and microglia microglia with Hb cultivating model, using 11.0T MRI and PET/CT imaging techniques, combined with immune coprecipitation, flow cytometry, immunofluorescence staining gobbling up hematoma, from the perspective of molecules, cells and animals, to prove thatCCL17/CCR4 regulates microglia polarization mediated hematoma removal after ICH through the ERK/AP1/SRA pathway, and to elucidate the mechanism of CCR4 targeting ERK/AP1/SRA pathway regulating microglia polarization mediated hematoma clearance, thereby to provide a new therapy target for ICH.