Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.
Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.
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DOI：
10.1016/j.immuni.2023.11.011
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发表时间：
2023-12
期刊：
影响因子：
32.4
通讯作者：
C. M. Wilk;F. Cathomas;Orsolya Török;Jessica Le Berichel;Matthew D. Park;Camille Bigenwald;George R. Heaton;Pauline Hamon;Leanna Troncoso;B. Scull;Diana K. Dangoor;Aymeric Silvin;Ryan Fleischmann;M. Belabed;Howard Lin;Elias Merad Taouli;Steffen Boettcher;Long Li;Antonio Aubry;M. Manz;Julia K. Kofler;Zhenyu Yue;Sérgio A. Lira;Florent Ginhoux;J. Crary;Kenneth L. McClain;Jennifer L. Picarsic;Scott J Russo;Carl E. Allen;M. Merad
中科院分区：
文献类型：
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作者：
C. M. Wilk;F. Cathomas;Orsolya Török;Jessica Le Berichel;Matthew D. Park;Camille Bigenwald;George R. Heaton;Pauline Hamon;Leanna Troncoso;B. Scull;Diana K. Dangoor;Aymeric Silvin;Ryan Fleischmann;M. Belabed;Howard Lin;Elias Merad Taouli;Steffen Boettcher;Long Li;Antonio Aubry;M. Manz;Julia K. Kofler;Zhenyu Yue;Sérgio A. Lira;Florent Ginhoux;J. Crary;Kenneth L. McClain;Jennifer L. Picarsic;Scott J Russo;Carl E. Allen;M. Merad
神经退行性疾病（ND）的特征在于神经元功能的进行性丧失。ND发病机制尚未完全了解，阻碍了有效治疗方法的发展。朗格汉斯细胞组织细胞增生症（LCH）是一种炎性肿瘤性疾病，由表达丝裂原活化蛋白激酶（MAPK）激活突变的造血祖细胞引起，这些突变分化为驱动病变形成的衰老骨髓细胞。一些患有LCH的个体随后发展为进行性和不可治愈的神经变性（LCH-ND）。在这里，我们发现LCH-ND是由与外周LCH细胞克隆的髓系细胞引起的。循环的BRAFV 600 E+髓样细胞导致血脑屏障（BBB）的破坏，增强了向脑实质的迁移，在脑实质中它们分化为在脑干和小脑中积累的衰老的炎性CD 11 a+巨噬细胞。阻断MAPK活性和衰老程序减少了临床前LCH-ND的外周炎症、脑实质浸润、神经炎症、神经元损伤和改善的神经学结果。循环髓样细胞中的MAPK活化和衰老程序代表LCH-ND的靶向机制。
Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. CirculatingBRAFV600E+myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND.