Evangelista Baggio A, Ragusa Joey V, Pellegrino Kyle, Wu Yijia, Quiroga-Barber Ivana Yoseli, Cahalan Shannon R, Arooji Omeed K, Madren Jillann A, Schroeter Sally, Cozzarin Joe, Xie Ling, Chen Xian, White Kristen K, Ezzell J Ashley, Iannone Marie A, Cohen Sarah, Phanstiel Douglas H, Meeker Rick B, Cohen Todd J
Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC, USA.
iScience. 2025 May 13;28(6):112648. doi: 10.1016/j.isci.2025.112648. eCollection 2025 Jun 20.
Amyotrophic lateral sclerosis (ALS) is the most common and fatal motor neuron disease. Approximately 90% of ALS patients exhibit pathology of the master RNA regulator, transactive response DNA binding protein (TDP-43). Despite the prevalence TDP-43 pathology in ALS motor neurons, recent findings suggest immune dysfunction is a determinant of disease progression in patients. Whether TDP-43 aggregates elicit immune responses remains underexplored. In this study, we demonstrate that TDP-43 aggregates are internalized by antigen-presenting cell populations, cause vesicle rupture, and drive innate and adaptive immune cell activation by way of antigen presentation. Using a multiplex imaging platform, we observed enrichment of activated microglia/macrophages in ALS white matter that correlated with phosphorylated TDP-43 accumulation, CD8 T cell infiltration, and major histocompatibility complex expression. Taken together, this study sheds light on a novel cellular response to TDP-43 aggregates through an immunological lens.
肌萎缩侧索硬化症（ALS）是最常见且致命的运动神经元疾病。约90%的ALS患者表现出主要RNA调节因子——反式激活应答DNA结合蛋白（TDP - 43）的病理学改变。尽管TDP - 43病理学在ALS运动神经元中普遍存在，但最近的研究结果表明免疫功能障碍是患者疾病进展的一个决定因素。TDP - 43聚集体是否引发免疫反应仍未得到充分探索。在本研究中，我们证明TDP - 43聚集体被抗原呈递细胞群体内化，导致囊泡破裂，并通过抗原呈递驱动先天性和适应性免疫细胞激活。使用多重成像平台，我们观察到ALS白质中活化的小胶质细胞/巨噬细胞富集，这与磷酸化TDP - 43积累、CD8 T细胞浸润和主要组织相容性复合体表达相关。综上所述，本研究通过免疫学视角揭示了对TDP - 43聚集体的一种新型细胞反应。
