Barcelona Pablo F, Sitaras Nicholas, Galan Alba, Esquiva Gema, Jmaeff Sean, Jian Yifan, Sarunic Marinko V, Cuenca Nicolas, Sapieha Przemyslaw, Saragovi H Uri
Lady Davis Institute-Jewish General Hospital, Center for Translational Research, McGill University, Montreal, Quebec H3T 1E2, Canada, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec H3G 1Y6, Canada.
Department of Ophthalmology, Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada.
J Neurosci. 2016 Aug 24;36(34):8826-41. doi: 10.1523/JNEUROSCI.4278-15.2016.
In many diseases, expression and ligand-dependent activity of the p75(NTR) receptor can promote pericyte and vascular dysfunction, inflammation, glial activation, and neurodegeneration. Diabetic retinopathy (DR) is characterized by all of these pathological events. However, the mechanisms by which p75(NTR) may be implicated at each stage of DR pathology remain poorly understood. Using a streptozotocin mouse model of diabetic retinopathy, we report that p75(NTR) is upregulated very early in glia and in pericytes to mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood-retina barrier breakdown, edema, and neuronal death. In a mouse model of oxygen-induced retinopathy, mimicking proliferative DR, p75(NTR)-dependent inflammation leads to ischemia and pathological angiogenesis through Semaphorin 3A. The acute use of antagonists of p75(NTR) or antagonists of the ligand proNGF suppresses each distinct phase of pathology, ameliorate disease, and prevent disease progression. Thus, our study documents novel disease mechanisms and validates druggable targets for diabetic retinopathy.
Diabetic retinopathy (DR) affects an estimated 250 million people and has no effective treatment. Stages of progression comprise pericyte/vascular dysfunction, inflammation, glial activation, and neurodegeneration. The pathophysiology of each stage remains unclear. We postulated that the activity of p75NTR may be implicated. We show that p75NTR in glia and in pericytes mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood-retina barrier breakdown, edema, and neuronal death. p75NTR-promoted inflammation leads to ischemia and angiogenesis through Semaphorin 3A. Antagonists of p75NTR or antagonists of proNGF suppress each distinct phase of pathology, ameliorate disease, and prevent disease progression. Our study documents novel mechanisms in a pervasive disease and validates druggable targets for treatment.
在许多疾病中，p75（神经营养因子受体）受体的表达和配体依赖性活性可促进周细胞和血管功能障碍、炎症、神经胶质细胞激活及神经退行性变。糖尿病视网膜病变（DR）具有所有这些病理事件的特征。然而，p75（神经营养因子受体）在糖尿病视网膜病变病理各阶段可能涉及的机制仍知之甚少。利用链脲佐菌素诱导的糖尿病视网膜病变小鼠模型，我们报告p75（神经营养因子受体）在神经胶质细胞和周细胞中很早就上调，以介导配体依赖性炎症细胞因子的诱导、神经-胶质-血管单元的破坏、血视网膜屏障的破坏、水肿和神经元死亡。在模拟增殖性糖尿病视网膜病变的氧诱导视网膜病变小鼠模型中，p75（神经营养因子受体）依赖性炎症通过信号素3A导致缺血和病理性血管生成。急性使用p75（神经营养因子受体）拮抗剂或配体前体神经生长因子（proNGF）拮抗剂可抑制病理的各个不同阶段，改善疾病并预防疾病进展。因此，我们的研究记录了新的疾病机制，并验证了糖尿病视网膜病变的可药物治疗靶点。
糖尿病视网膜病变（DR）估计影响2.5亿人，且没有有效的治疗方法。疾病进展阶段包括周细胞/血管功能障碍、炎症、神经胶质细胞激活和神经退行性变。每个阶段的病理生理学仍不清楚。我们推测p75神经营养因子受体的活性可能与之有关。我们表明，神经胶质细胞和周细胞中的p75神经营养因子受体介导配体依赖性炎症细胞因子的诱导、神经-胶质-血管单元的破坏、血视网膜屏障的破坏、水肿和神经元死亡。p75神经营养因子受体促进的炎症通过信号素3A导致缺血和血管生成。p75神经营养因子受体拮抗剂或proNGF拮抗剂可抑制病理的各个不同阶段，改善疾病并预防疾病进展。我们的研究记录了一种普遍疾病中的新机制，并验证了可用于治疗的药物靶点。
