García-Fernández Patricia, Üçeyler Nurcan, Sommer Claudia
Department of Neurology, University Hospital of Würzburg, Würzburg, Germany.
Pain Rep. 2021 Mar 9;6(1):e898. doi: 10.1097/PR9.0000000000000898. eCollection 2021.
This review describes the roles of the low-density lipoprotein receptor-related protein 1 (LRP-1) in inflammatory pathways, nerve nerve degeneration and -regeneration and in neuropathic pain. Induction of LRP-1 is able to reduce the activation of the proinflammatory NFκB-mediated pathway and the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase and p38 signaling pathways, in turn decreasing the production of inflammatory mediators. Low-density lipoprotein receptor-related protein 1 activation also decreases reactive astrogliosis and polarizes microglial cells and macrophages from a proinflammatory phenotype (M1) to an anti-inflammatory phenotype (M2), attenuating the neuroinflammatory environment. Low-density lipoprotein receptor-related protein 1 can also modulate the permeability of the blood-brain barrier and the blood-nerve barrier, thus regulating the infiltration of systemic insults and cells into the central and the peripheral nervous system, respectively. Furthermore, LRP-1 is involved in the maturation of oligodendrocytes and in the activation, migration, and repair phenotype of Schwann cells, therefore suggesting a major role in restoring the myelin sheaths upon injury. Low-density lipoprotein receptor-related protein 1 activation can indirectly decrease neurodegeneration and neuropathic pain by attenuation of the inflammatory environment. Moreover, LRP-1 agonists can directly promote neural cell survival and neurite sprouting, decrease cell death, and attenuate pain and neurological disorders by the inhibition of MAPK c-Jun N-terminal kinase and p38-pathway and activation of MAPK extracellular signal-regulated kinase pathway. In addition, activation of LRP-1 resulted in better outcomes for neuropathies such as Alzheimer disease, nerve injury, or diabetic peripheral neuropathy, attenuating neuropathic pain and improving cognitive functions. To summarize, LRP-1 plays an important role in the development of different experimental diseases of the nervous system, and it is emerging as a very interesting therapeutic target.
本综述描述了低密度脂蛋白受体相关蛋白1（LRP-1）在炎症途径、神经退变与再生以及神经性疼痛中的作用。LRP-1的诱导能够降低促炎的核因子κB（NFκB）介导途径以及丝裂原活化蛋白激酶（MAPK）c-Jun氨基末端激酶和p38信号通路的激活，进而减少炎症介质的产生。低密度脂蛋白受体相关蛋白1的激活还能减少反应性星形胶质细胞增生，并使小胶质细胞和巨噬细胞从促炎表型（M1）极化为抗炎表型（M2），减轻神经炎症环境。低密度脂蛋白受体相关蛋白1还可调节血脑屏障和血神经屏障的通透性，从而分别调节全身损伤和细胞向中枢神经系统和周围神经系统的浸润。此外，LRP-1参与少突胶质细胞的成熟以及雪旺细胞的激活、迁移和修复表型，因此提示其在损伤后恢复髓鞘方面发挥主要作用。低密度脂蛋白受体相关蛋白1的激活可通过减轻炎症环境间接减少神经退变和神经性疼痛。此外，LRP-1激动剂可直接促进神经细胞存活和神经突发芽，减少细胞死亡，并通过抑制MAPK c-Jun氨基末端激酶和p38途径以及激活MAPK细胞外信号调节激酶途径减轻疼痛和神经功能障碍。此外，LRP-1的激活对诸如阿尔茨海默病、神经损伤或糖尿病性周围神经病等神经病变产生更好的结果，减轻神经性疼痛并改善认知功能。总之，LRP-1在不同的神经系统实验性疾病的发展中起重要作用，并且正成为一个非常有吸引力的治疗靶点。
