Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.
Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.
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DOI：
10.1186/s12974-022-02629-1
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发表时间：
2022-11-04
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
髓样细胞上表达的触发受体2（Trem 2）在神经退行性疾病中起保护作用。相比之下，Trem 2功能可能会在呼吸道病毒或肝脏感染期间加剧组织损伤。因此，我们研究了Trem 2在病毒性脑脊髓炎模型中的作用，该模型与显著的Th 1介导的抗病毒免疫相关，导致脱髓鞘。野生型（WT）和Trem 2缺陷型（Trem 2 −/−）小鼠颅内感染亚致死性嗜胶质鼠冠状病毒（MHV-JHM）。每天监测疾病进展和生存期。用流式细胞术和组织切片免疫荧光分析法检测脊髓（SC）中白细胞积聚和病理学特征，包括脱髓鞘和轴突损伤。通过RT-PCR测量选择的炎性细胞因子和趋化因子的表达，并且使用Nanostring nCounter平台确定SC衍生的小胶质细胞和浸润的骨髓衍生的巨噬细胞（BMDM）中的总体髓样细胞基因表达。与病毒对照的小胶质细胞相比，BMDM在感染后招募到SC中，高度上调Trem 2 mRNA。Trem 2缺乏并不改变疾病的发作或严重程度，但损害了脱髓鞘发作后的临床恢复。Trem 2 −/−小鼠的疾病进展不能归因于病毒控制的改变或促炎反应的升高。一个突出的差异是与髓样细胞标志物IBA 1和/或CD 68无关的变性髓鞘增加。SC衍生的小胶质细胞和BMDM的基因表达谱进一步揭示，Trem 2缺陷导致小胶质细胞中吞噬相关基因Lpl和Cd 36的上调受损，但在BMDM中的模式更复杂。病毒诱导的脱髓鞘过程中Trem 2缺陷会使其他选择的调节吞噬途径和脂质代谢的基因表达失调，对小胶质细胞和BMDM有明显影响。去除受损髓鞘的最终失败让人想起毒素或自身免疫细胞诱导的脱髓鞘模型，并支持Trem 2功能通过感测组织损伤来调节，包括在非常不同的炎症环境中失调的脂质环境。在线版本包含补充材料，可通过10.1186/s12974-022-02629-1获得。
Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. Wild-type (WT) and Trem2 deficient (Trem2−/−) mice were infected with a sublethal glia tropic murine coronavirus (MHV–JHM) intracranially. Disease progression and survival were monitored daily. Leukocyte accumulation and pathological features including demyelination and axonal damage in spinal cords (SC) were determined by flow cytometry and tissue section immunofluorescence analysis. Expression of select inflammatory cytokines and chemokines was measured by RT-PCR and global myeloid cell gene expression in SC-derived microglia and infiltrated bone-marrow-derived macrophages (BMDM) were determined using the Nanostring nCounter platform. BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2−/− mice could not be attributed to altered virus control or an elevated proinflammatory response. A prominent difference was increased degenerated myelin not associated with the myeloid cell markers IBA1 and/or CD68. Gene expression profiles of SC-derived microglia and BMDM further revealed that Trem2 deficiency resulted in impaired upregulation of phagocytosis associated genes Lpl and Cd36 in microglia, but a more complex pattern in BMDM. Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments. The online version contains supplementary material available at 10.1186/s12974-022-02629-1.
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影响因子：
5.1
作者：
Fu, Ruying;Shen, Qingyu;Xu, Pengfei;Luo, Jin Jun;Tang, Yamei
通讯作者：
Tang, Yamei
影响因子：
6.4
作者：
Hwang M;Phares TW;Hinton DR;Stohlman SA;Bergmann CC;Min B
通讯作者：
Min B
DOI：
10.1084/jem.20142322
发表时间：
2015-03-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Jay TR;Miller CM;Cheng PJ;Graham LC;Bemiller S;Broihier ML;Xu G;Margevicius D;Karlo JC;Sousa GL;Cotleur AC;Butovsky O;Bekris L;Staugaitis SM;Leverenz JB;Pimplikar SW;Landreth GE;Howell GR;Ransohoff RM;Lamb BT
通讯作者：
Lamb BT
影响因子：
5.4
作者：
FLEMING, JO;TROUSDALE, MD;WEINER, LP
通讯作者：
WEINER, LP
影响因子：
12.7
作者：
Cignarella, Francesca;Filipello, Fabia;Piccio, Laura
通讯作者：
Piccio, Laura