Department of Anatomy and Cell Biology, RWTH Aachen University, Aachen, Germany.
J Neurochem. 2010 May;113(3):749-60. doi: 10.1111/j.1471-4159.2010.06637.x. Epub 2010 Feb 5.
Recent studies suggest that the chemotactic G protein-coupled receptor formyl-peptide-receptor-like-1 (FPRL1) or the scavenger receptor MARCO (macrophage receptor with collagenous structure) plays an essential role in the inflammatory response of host defense mechanisms and neurodegenerative disorders such as Alzheimer's disease. We therefore analyzed the involvement of FPRL1 and MARCO in amyloid beta1-42 (Abeta1-42)-induced signalling by extracellular-signal regulated kinases 1/2 (ERK1/2) phosphorylation and cAMP level measurement in glial cells (astrocytes and microglia) and in transfected HEK293 cells. Receptors were inhibited by small interference RNA and the consequences in Abeta1-42- and MARCO agonist fucoidan-induced signal transduction were determined. Receptor deactivation by antagonists or small interference RNA verified the importance of FPRL1 for Abeta1-42-mediated signal transduction by ERK1/2 phosphorylation and cAMP level measurement in glial cells. Furthermore, for the first time, we have demonstrated a functional interaction between FPRL1 and scavenger receptors in fucoidan-mediated signalling by ERK1/2 phosphorylation and cAMP level measurement. In addition, co-immunoprecipitation data and fluorescence microscopy measurements revealed a physical interaction between FPR, FPRL1 and MARCO. These results suggest that FPRL1 plays a pivotal role for Abeta1-42-induced signal transduction in glial cells and the interaction with MARCO could explain the broad ligand spectrum of formyl peptide receptors.
最近的研究表明，趋化性 G 蛋白偶联受体甲酰肽受体样 1（FPRL1）或清道夫受体 MARCO（具有胶原结构的巨噬细胞受体）在宿主防御机制的炎症反应和神经退行性疾病（如阿尔茨海默病）中发挥重要作用。因此，我们分析了 FPRL1 和 MARCO 在淀粉样蛋白β1-42（Aβ1-42）诱导的信号转导中的作用，通过细胞外信号调节激酶 1/2（ERK1/2）磷酸化和 cAMP 水平测量来研究神经胶质细胞（星形胶质细胞和小胶质细胞）和转染的 HEK293 细胞。通过小干扰 RNA 抑制受体，并确定 Aβ1-42 和 MARCO 激动剂褐藻糖胶诱导的信号转导中受体失活的后果。通过拮抗剂或小干扰 RNA 使受体失活，验证了 FPRL1 在 Aβ1-42 介导的 ERK1/2 磷酸化和 cAMP 水平测量的信号转导中的重要性。此外，我们首次证明了 FPRL1 在褐藻糖胶介导的信号转导中与清道夫受体之间存在功能性相互作用，通过 ERK1/2 磷酸化和 cAMP 水平测量。此外，共免疫沉淀数据和荧光显微镜测量显示了 FPR、FPRL1 和 MARCO 之间的物理相互作用。这些结果表明，FPRL1 在神经胶质细胞中 Aβ1-42 诱导的信号转导中起着关键作用，与 MARCO 的相互作用可以解释甲酰肽受体的广泛配体谱。
