Division of Neuroimmunology, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, United States.
Department of Neurology, University of Pittsburgh, Pittsburgh, United States.
Elife. 2024 Oct 30;12:RP88414. doi: 10.7554/eLife.88414.
While modern high efficacy disease modifying therapies have revolutionized the treatment of relapsing-remitting multiple sclerosis, they are less effective at controlling progressive forms of the disease. Meningeal inflammation is a recognized risk factor for cortical gray matter pathology which can result in disabling symptoms such as cognitive impairment and depression, but the mechanisms linking meningeal inflammation and gray matter pathology remain unclear. Here, we performed magnetic resonance imaging (MRI)-guided spatial transcriptomics in a mouse model of autoimmune meningeal inflammation to characterize the transcriptional signature in areas of meningeal inflammation and the underlying brain parenchyma. We found broadly increased activity of inflammatory signaling pathways at sites of meningeal inflammation, but only a subset of these pathways active in the adjacent brain parenchyma. Subclustering of regions adjacent to meningeal inflammation revealed the subset of immune programs induced in brain parenchyma, notably complement signaling and antigen processing/presentation. Trajectory gene and gene set modeling analysis confirmed variable penetration of immune signatures originating from meningeal inflammation into the adjacent brain tissue. This work contributes a valuable data resource to the field, provides the first detailed spatial transcriptomic characterization in a model of meningeal inflammation, and highlights several candidate pathways in the pathogenesis of gray matter pathology.
虽然现代高效的疾病修正疗法已经彻底改变了复发性缓解型多发性硬化症的治疗方法，但它们在控制进行性疾病方面的效果较差。脑膜炎症是皮质灰质病理学的公认危险因素，可导致认知障碍和抑郁等致残症状，但脑膜炎症和灰质病理学之间的联系机制仍不清楚。在这里，我们在自身免疫性脑膜炎症的小鼠模型中进行了磁共振成像（MRI）引导的空间转录组学研究，以描述脑膜炎症区域和潜在脑实质中的转录特征。我们发现脑膜炎症部位的炎症信号通路广泛激活，但只有一部分通路在相邻的脑实质中活跃。与脑膜炎症相邻的区域的亚聚类揭示了在脑实质中诱导的免疫程序子集，特别是补体信号和抗原加工/呈递。轨迹基因和基因集建模分析证实，源自脑膜炎症的免疫特征在相邻脑组织中的渗透程度不同。这项工作为该领域提供了有价值的数据源，首次对脑膜炎症模型进行了详细的空间转录组学描述，并突出了灰质病理学发病机制中的几个候选途径。
