Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.
Type 1 interferon mediates chronic stress-induced neuroinflammation and behavioral deficits via complement component 3-dependent pathway.
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DOI：
10.1038/s41380-021-01065-6
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发表时间：
2021-07
影响因子：
11
通讯作者：
Pillai A
中科院分区：
文献类型：
--
作者：
Tripathi A;Whitehead C;Surrao K;Pillai A;Madeshiya A;Li Y;Khodadadi H;Ahmed AO;Turecki G;Baban B;Pillai A
慢性应激是许多神经精神疾病病理生理学中的一个主要危险因素。此外，在人类和动物模型中，慢性应激条件可以促进神经炎症和炎症反应。I型干扰素（IFN-I）是外周炎症反应的关键介质，并负责改变情绪和行为。然而，其潜在机制尚不清楚。在本研究中，我们研究了IFN-I信号在慢性应激诱导的神经炎症和行为变化中的作用。通过慢性抑制应激模型，我们发现慢性应激诱导小鼠血清IFNβ水平显著升高，全身阻断IFN-I信号通路可减轻慢性应激诱导的巨噬细胞向前额叶皮层的浸润和行为异常。此外，补体成分3 （C3）介导全身ifn β诱导的神经炎症和行为改变。此外，我们还发现抑郁自杀者前额叶皮层IFN-I刺激基因mRNA表达水平显著升高，并与C3和炎症标志物显著相关。总之，这些来自动物和人类死后大脑研究的发现确定了C3在慢性应激条件下ifn - i介导的神经炎症和行为变化中的关键作用。
Chronic stress is a major risk factor in the pathophysiology of many neuropsychiatric disorders. Further, chronic stress conditions can promote neuroinflammation and inflammatory responses in both humans and animal models. Type I interferons (IFN-I) are critical mediators of the inflammatory response in the periphery and responsible for the altered mood and behavior. However, the underlying mechanisms are not well understood. In the present study, we investigated the role of IFN-I signaling in chronic stress-induced changes in neuroinflammation and behavior. Using the chronic restraint stress model, we found that chronic stress induces a significant increase in serum IFNβ levels in mice, and systemic blockade of IFN-I signaling attenuated chronic stress-induced infiltration of macrophages into prefrontal cortex and behavioral abnormalities. Furthermore, complement component 3 (C3) mediates systemic IFNβ-induced changes in neuroinflammation and behavior. Also, we found significant increases in the mRNA expression levels of IFN-I stimulated genes in the prefrontal cortex of depressed suicide subjects and significant correlation with C3 and inflammatory markers. Together, these findings from animal and human postmortem brain studies identify a crucial role of C3 in IFN-I-mediated changes in neuroinflammation and behavior under chronic stress conditions.
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