脊髓损伤后浸润巨噬细胞内髓鞘源性脂质代谢的机制以及MIF的调控作用

A large number of lipid rich myelin debris was produced in the injured spinal cord. However, there is a lack of studies on the mechanism of lipid metabolism. Recent studies have shown that myelin lipids are important regulators of axon regeneration. We found that the infiltrating bone marrow derived macrophages (BMDMs) are the major sites for the phagocytosis and metabolism of myelin lipids. The balance of intracellular lipid metabolism was disrupted, which induced the accumulation of cholesterol within the BMDMs, and then the foamy cells formed. These foamy cells persisted in the pro-inflammatory phenotype M1. Myelin debris up-regulated ABCA1 being responsible for reverse cholesterol transport. The up-regulation of ABCA1 accelerated cholesterol efflux from BMDMs. Macrophage migration inhibitory factor (MIF) knockdown inhibited ABCA1 expression significantly. We think that acceleration of cholesterol efflux can terminate M1, and promote M2 phenotype, which will be beneficial for spinal cord regeneration and repair. ABCA1 is a therapeutic target for effective intervention. MIF is involved in the regulation of intracellular lipid metabolism by regulating the expression of ABCA1. In this project, we will focus on ABCA1 to elucidate myelin derived lipid metabolism in macrophages and the regulation of MIF in molecular, cellular and in vivo levels to further clarify the mechanism of spinal cord injury and repair. This project will provide valuable therapeutic strategies for clinical practice, and be of great theoretical and clinical significance.

脊髓损伤部位产生大量富含脂质的髓鞘碎片，然而对髓鞘脂质代谢机制却缺乏研究。但新近研究发现髓鞘脂质是一类重要的轴突再生调节子。我们发现浸润至损伤中心的骨髓源性巨噬细胞（BMDMs）是吞噬和代谢髓鞘脂质的主要场所，损伤中心BMDMs内脂质代谢紊乱，胆固醇积聚，形成泡沫细胞，使BMDMs持久保持在M1促炎表型；髓鞘碎片上调负责胆固醇逆转运的ABCA1，ABCA1上调促进胆固醇外流；巨噬细胞移动因子（MIF）敲除严重抑制ABCA1表达。我们认为，加速胆固醇排出，可终止M1表型，促进M2表型，有利于脊髓再生修复；ABCA1是可以进行有效干预的治疗靶点，MIF可调控ABCA1表达，从而参与调控细胞内脂质代谢。本课题将以ABCA1为研究靶点，在分子、细胞和在体水平阐明BMDMs内髓鞘脂代谢机制以及MIF的调控作用，以进一步揭示脊髓损伤与修复的本质，为临床提供有价值的治疗策略，具有重要理论和临床指导意义。

由于脊髓损伤后神经元不能再生，造成脊髓损伤病人终身瘫痪，感觉和运动功能障碍，甚至影响认知功能。脊髓含大量髓鞘，髓鞘富含脂质，造成脊髓损伤部位脂质堆积，然而对髓鞘脂质代谢机制却缺乏研究。本研究发现浸润至损伤中心的骨髓源性巨噬细胞（BMDMs）是吞噬和代谢髓鞘脂质的主要场所，损伤中心BMDMs内脂质代谢紊乱，胆固醇积聚，形成泡沫细胞，使BMDMs持久保持在促炎性功能表型，引起脊髓继发性损伤加重。具有功能多样性的巨噬细胞移动抑制因子（Macrophage migration inhibitory factor，MIF），脊髓损伤后显著增高，加速脂质代谢；进一步发现MIF敲除可以显著抑制负责胆固醇逆转运的腺苷三磷酸结合盒转运体（ABC）A1的表达，造成脂质堆积。敲除ABCA1则造成脊髓损伤部位严重脂质堆积，而上调ABCA1可以促进脂质代谢，并改善BMDMs功能表型，涉及广泛的细胞内外生物功能过程，不仅激活免疫系统功能，改变炎症和免疫反应过程，影响和调控先天性免疫反应，调控T淋巴细胞和B淋巴细胞功能活动，调控吞噬功能，而且调节神经发生、神经元分化、迁移和投射，轴突发育、延伸和导向、突触形成和活动、信号传递，神经元轴突的髓鞘化，胶质发生，神经元凋亡，影响血管生成,疤痕形成等等，均发生显著改变。经过干预的BMDMs提高了运动、感觉和认知功能，有利于脊髓损伤后的再生修复。因此，ABCA1是可以进行有效干预的治疗靶点。本课题进一步揭示脊髓损伤与修复的本质，为临床提供有价值的治疗策略，具有重要理论和临床指导意义。