TNFR2 Signaling Regulates the Immunomodulatory Function of Oligodendrocyte Precursor Cells.
TNFR2 Signaling Regulates the Immunomodulatory Function of Oligodendrocyte Precursor Cells.
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DOI：
10.3390/cells10071785
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发表时间：
2021-07-15
期刊：
影响因子：
6
通讯作者：
Brambilla R
中科院分区：
文献类型：
--
作者：
Desu HL;Illiano P;Choi JS;Ascona MC;Gao H;Lee JK;Brambilla R
多发性硬化症（MS）是一种以炎症、中枢神经系统脱髓鞘和进行性神经变性为特征的神经免疫疾病。慢性多发性硬化症患者表现出髓鞘再生能力受损，部分原因是由于少突胶质前体细胞（OPCs）对多发性硬化症病变环境的反应发生了变化。细胞因子肿瘤坏死因子（TNF）存在于ms影响的中枢神经系统中，并与疾病病理生理有关。在两种活性形式的TNF，跨膜（tmTNF）和可溶性（solTNF）中，tmTNF通过TNFR2信号介导保护和修复作用，包括髓鞘再生，而solTNF主要通过TNFR1信号促进神经毒性。为了更好地理解MS修复失败的机制，我们研究了OPCs对炎症暴露的细胞反应以及TNFR2信号在其调节中的特定作用。在用IFNγ、il - 1β和TNF处理培养的OPCs后，我们通过RNA测序观察到，OPCs明显的炎症和免疫激活，伴随着代谢变化和增殖和分化程序失调。我们还确定了在神经炎症条件下，OPCs与小胶质细胞之间的细胞间相互作用的可能性很高，OPCs能够产生可以招募和激活小胶质细胞的趋化因子。重要的是，我们发现当TNFR2消融时，这些功能会加剧。总之，我们的数据表明，神经炎症导致OPCs向免疫调节表型转变，同时降低其增殖和分化的能力，从而损害其修复功能。此外，我们证明TNFR2在这一过程中起关键作用，这表明促进TNFR2激活或其下游信号可能是恢复脱髓鞘疾病中OPC修复能力的有效策略。
Multiple sclerosis (MS) is a neuroimmune disorder characterized by inflammation, CNS demyelination, and progressive neurodegeneration. Chronic MS patients exhibit impaired remyelination capacity, partly due to the changes that oligodendrocyte precursor cells (OPCs) undergo in response to the MS lesion environment. The cytokine tumor necrosis factor (TNF) is present in the MS-affected CNS and has been implicated in disease pathophysiology. Of the two active forms of TNF, transmembrane (tmTNF) and soluble (solTNF), tmTNF signals via TNFR2 mediating protective and reparative effects, including remyelination, whereas solTNF signals predominantly via TNFR1 promoting neurotoxicity. To better understand the mechanisms underlying repair failure in MS, we investigated the cellular responses of OPCs to inflammatory exposure and the specific role of TNFR2 signaling in their modulation. Following treatment of cultured OPCs with IFNγ, IL1β, and TNF, we observed, by RNA sequencing, marked inflammatory and immune activation of OPCs, accompanied by metabolic changes and dysregulation of their proliferation and differentiation programming. We also established the high likelihood of cell–cell interaction between OPCs and microglia in neuroinflammatory conditions, with OPCs able to produce chemokines that can recruit and activate microglia. Importantly, we showed that these functions are exacerbated when TNFR2 is ablated. Together, our data indicate that neuroinflammation leads OPCs to shift towards an immunomodulatory phenotype while diminishing their capacity to proliferate and differentiate, thus impairing their repair function. Furthermore, we demonstrated that TNFR2 plays a key role in this process, suggesting that boosting TNFR2 activation or its downstream signals could be an effective strategy to restore OPC reparative capacity in demyelinating disease.
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影响因子：
8.8
作者：
Gao H;Danzi MC;Choi CS;Taherian M;Dalby-Hansen C;Ellman DG;Madsen PM;Bixby JL;Lemmon VP;Lambertsen KL;Brambilla R
通讯作者：
Brambilla R
影响因子：
12.4
作者：
Bonora, M.;De Marchi, E.;Pinton, P.
通讯作者：
Pinton, P.
影响因子：
5.3
作者：
Balabanov, Roumen;Strand, Krystle;Popko, Brian
通讯作者：
Popko, Brian
DOI：
10.1084/jem.170.2.607
发表时间：
1989-08-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hofman FM;Hinton DR;Johnson K;Merrill JE
通讯作者：
Merrill JE
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser