美国西奈山伊坎医学院Miriam Merad团队发现，循环衰老髓系细胞浸润大脑并导致组织细胞疾病的神经变性。该项研究成果于2023年12月12日发表在《免疫》杂志上。

研究人员表示，神经退行性疾病（ND）的特征是神经元功能的逐渐丧失。神经退行性疾病的发病机制尚不完全清楚，阻碍了有效疗法的开发。朗格汉斯细胞组织细胞增生症（Langerhans cell histiocytosis，LCH）是一种炎症性肿瘤性疾病，由表达有丝分裂原激活蛋白激酶（MAPK）激活突变的造血祖细胞分化成衰老的髓样细胞并驱动病变形成所致。一些LCH患者随后发展为进行性和不可治愈的神经变性（LCH-ND）。

研究人员发现LCH-ND是由与外周LCH细胞具有克隆性的髓样细胞引起的。循环中的BRAFV600E⁺髓系细胞会导致血脑屏障（BBB）破裂，促进向脑实质的迁移，在那里它们会分化成衰老的、具有炎症性的CD11a⁺巨噬细胞，并在脑干和小脑中聚集。阻断MAPK活性和衰老程序可减少外周炎症、脑实质浸润、神经炎症、神经元损伤，并改善临床前LCH-ND的神经系统预后。循环髓系细胞中的MAPK激活和衰老程序代表了LCH-ND的靶向机制。

附：英文原文

Title: Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders

Author: C. Matthias Wilk, Flurin Cathomas, Orsolya Trk, Jessica Le Berichel, Matthew D. Park, Camille Bigenwald, George R. Heaton, Pauline Hamon, Leanna Troncoso, Brooks P. Scull, Diana Dangoor, Aymeric Silvin, Ryan Fleischmann, Meriem Belabed, Howard Lin, Elias Merad Taouli, Steffen Boettcher, Long Li, Antonio Aubry, Markus G. Manz, Julia K. Kofler, Zhenyu Yue, Sergio A. Lira, Florent Ginhoux, John F. Crary, Kenneth L. McClain, Jennifer L. Picarsic, Scott J. Russo, Carl E. Allen, Miriam Merad

Issue&Volume: 2023/12/12

Abstract: Neurodegenerative diseases (ND) are characterized by progressive loss of neuronalfunction. Mechanisms of ND pathogenesis are incompletely understood, hampering thedevelopment of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatoryneoplastic disorder caused by hematopoietic progenitors expressing mitogen-activatedprotein kinase (MAPK)-activating mutations that differentiate into senescent myeloidcells that drive lesion formation. Some individuals with LCH subsequently developprogressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-NDwas caused by myeloid cells that were clonal with peripheral LCH cells. CirculatingBRAFV600E+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migrationinto the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activityand senescence programs reduced peripheral inflammation, brain parenchymal infiltration,neuroinflammation, neuronal damage and improved neurological outcome in preclinicalLCH-ND. MAPK activation and senescence programs in circulating myeloid cells representtargetable mechanisms of LCH-ND.

DOI: 10.1016/j.immuni.2023.11.011

Source: https://www.cell.com/immunity/fulltext/S1074-7613(23)00493-4