TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease

IF 8.8 2区 医学 Q1 IMMUNOLOGY
Haritha L. Desu , Estrid Thougaard , Brianna N. Carney , Placido Illiano , Melanie J. Plastini , Yoleinny Florimon , Antonella Mini , Chelsea Guastucci , Brian Kang , Jae K. Lee , Kate L. Lambertsen , Roberta Brambilla
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Abstract

Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated “foamy” phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

Abstract Image

在中枢神经系统脱髓鞘疾病中,少突胶质前体细胞中的 TNFR2 信号可抑制其免疫炎症功能和有害的小胶质细胞激活。
多发性硬化症(MS)是中枢神经系统(CNS)的一种慢性退行性疾病,以炎症、脱髓鞘和进行性神经变性为特征。这些过程加上少突胶质细胞前体细胞(OPCs)启动的修复性再髓鞘化失败,导致不可逆转的神经损伤。细胞因子肿瘤坏死因子(TNF)通过激活神经胶质中的同源受体 TNFR2 而参与中枢神经系统的修复。在这里,我们证明了 TNFR2 在脱髓鞘疾病期间调节体内 OPC 功能的重要作用,并证明在 OPC 中表达的 TNFR2 可调节 OPC 与小胶质细胞之间的相互作用。在选择性消减OPCs中TNFR2的PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp小鼠中,我们观察到实验性自身免疫性脑脊髓炎(EAE)的发病时间和疾病高峰提前。这与脊髓中免疫细胞浸润加速和小胶质细胞活化增加有关。同样,与对照组小鼠相比,PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp小鼠在铜绿素诱导脱髓鞘后,胼胝体中的小胶质细胞反应性迅速增强,随后成熟的髓鞘化少突胶质细胞(OLs)数量长期减少。结合EAE和铜绿素模型,我们发现TNFR2在OPC分化中没有细胞自主作用,但可能对新形成的成熟OLs的存活很重要。最后,我们利用体外方法证明,当与富含髓鞘的脊髓匀浆一起培养时,Tnfrsf1b 消减的 OPCs 释放的因子会促使小胶质细胞形成加剧的 "泡沫 "表型,并异常增加溶酶体脂质的积累。总之,我们的数据表明,OPCs 中的 TNFR2 信号通过抑制其免疫炎症活化和抑制神经毒性小胶质细胞反应性而起到保护作用。这表明,在神经免疫和脱髓鞘疾病中,促进 TNFR2 或其下游级联的活化可能是恢复 OPC 修复能力的有效策略。
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来源期刊
CiteScore
29.60
自引率
2.00%
发文量
290
审稿时长
28 days
期刊介绍: Established in 1987, Brain, Behavior, and Immunity proudly serves as the official journal of the Psychoneuroimmunology Research Society (PNIRS). This pioneering journal is dedicated to publishing peer-reviewed basic, experimental, and clinical studies that explore the intricate interactions among behavioral, neural, endocrine, and immune systems in both humans and animals. As an international and interdisciplinary platform, Brain, Behavior, and Immunity focuses on original research spanning neuroscience, immunology, integrative physiology, behavioral biology, psychiatry, psychology, and clinical medicine. The journal is inclusive of research conducted at various levels, including molecular, cellular, social, and whole organism perspectives. With a commitment to efficiency, the journal facilitates online submission and review, ensuring timely publication of experimental results. Manuscripts typically undergo peer review and are returned to authors within 30 days of submission. It's worth noting that Brain, Behavior, and Immunity, published eight times a year, does not impose submission fees or page charges, fostering an open and accessible platform for scientific discourse.
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