Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1.
Astrocyte interferon-gamma signaling dampens inflammation during chronic central nervous system autoimmunity via PD-L1.
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DOI：
10.1186/s12974-023-02917-4
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发表时间：
2023-10-12
影响因子：
9.3
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中科院分区：
文献类型：
--
作者：
多发性硬化症（MS）是一种中枢神经系统（CNS）的炎症和神经退行性疾病。浸润性炎症免疫细胞会导致中枢神经系统脱髓鞘和轴突损伤持续存在，并显着导致病理和临床缺陷。虽然细胞因子干扰素 (IFN)γ 通常被描述为对急性中枢神经系统自身免疫有害，但我们和其他人已经证明星形细胞 IFNγ 信号传导也具有神经保护作用。在这里，我们对 IFNγ 处理的星形胶质细胞进行了 RNA 测序和独创性通路分析，发现 PD-L1 显着表达。有趣的是，PD-1/PD-L1 拮抗作用减少了体外暴露于 IFNγ 处理的星形胶质细胞的白细胞的凋亡。为了进一步阐明体内星形细胞 IFNγ 信号对 PD-1/PD-L1 轴的作用，我们在 Aldh1l1-CreERT2、Ifngr1fl/fl 小鼠中诱导了 MS 实验性自身免疫性脑脊髓炎 (EAE) 模型。条件性星形细胞缺失 IFNγ 受体的小鼠表现出 PD-L1 表达减少，这与浸润性白细胞（尤其是骨髓系的浸润性白细胞）增加相对应，并加剧了临床疾病。 PD-1 激动剂可降低 EAE 严重程度和 CNS 浸润白细胞。重要的是，PD-1 由多发性硬化症病变周围的骨髓细胞表达。这些数据支持星形胶质细胞中的 IFNγ 信号传导通过上调 PD-L1 来减轻慢性自身免疫期间的炎症，这表明对多发性硬化症患者具有潜在的治疗益处。在线版本包含可在 10.1186/s12974-023-02917-4 获取的补充材料。
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. While the cytokine interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. Here, we performed RNA sequencing and ingenuity pathway analysis on IFNγ-treated astrocytes and found that PD-L1 was prominently expressed. Interestingly, PD-1/PD-L1 antagonism reduced apoptosis in leukocytes exposed to IFNγ-treated astrocytes in vitro. To further elucidate the role of astrocytic IFNγ signaling on the PD-1/PD-L1 axis in vivo, we induced the experimental autoimmune encephalomyelitis (EAE) model of MS in Aldh1l1-CreERT2, Ifngr1fl/fl mice. Mice with conditional astrocytic deletion of IFNγ receptor exhibited a reduction in PD-L1 expression which corresponded to increased infiltrating leukocytes, particularly from the myeloid lineage, and exacerbated clinical disease. PD-1 agonism reduced EAE severity and CNS-infiltrating leukocytes. Importantly, PD-1 is expressed by myeloid cells surrounding MS lesions. These data support that IFNγ signaling in astrocytes diminishes inflammation during chronic autoimmunity via upregulation of PD-L1, suggesting potential therapeutic benefit for MS patients. The online version contains supplementary material available at 10.1186/s12974-023-02917-4.
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