Microglial priming by IFN-γ involves STAT1-mediated activation of the NLRP3 inflammasome

IF 4.8 1区医学 Q1 NEUROSCIENCES CNS Neuroscience & Therapeutics Pub Date : 2024-10-11 DOI:10.1111/cns.70061

Haili He, Xiaomei Zhang, Hui He, Gaojie Xu, Liangyuan Li, Chengyan Yang, Yu-e Liu, Zili You, Jinqiang Zhang

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Abstract

Background

Inflammatory and immune responses in the brain that contribute to various neuropsychiatric disorders may begin as microglial “priming”. Interferon (IFN)-γ is known to cause microglial priming, but the mechanism is unclear.

Methods

We examined the effects of IFN-γ on gene expression, microglial activation, inflammatory and immune responses and activity of the NLRP3 inflammasome in primary microglia and in the brains of mice.

Results

Our results showed that treating microglial cultures with IFN-γ induced a hedgehog-like morphology and upregulated markers of microglial activation (CD86, CD11b) and pro-inflammatory molecules (IL-1β, IL-6, TNF-α, iNOS), while downregulating markers of microglial homeostasis (CX3CR1, CD200R1), anti-inflammatory molecules (MCR1, Arg-1) and neurotrophic factors (IGF-1, BDNF). IFN-γ also upregulated markers of NLRP3 inflammasome activation (NLRP3, caspase-1, gasdermin D, IL-18). This particular transcriptional profiling makes IFN-γ-primed microglia with exaggerated responses upon lipopolysaccharide (LPS) stimulation. The level of NLRP3, caspase-1, gasdermin D, IL-1β, IL-18, TNF-α and iNOS in microglia cultures treated with both IFN-γ and LPS were highest than with either one alone. Injecting IFN-γ into the lateral ventricle of mice induced similar morphological and functional changes in hippocampal microglia as in primary microglial cultures. The effects of IFN-γ on NLRP3 inflammasome and microglia from cultures or hippocampus were abolished when STAT1 was inhibited using fludarabin. Injecting mice with IFN-γ alone or together with LPS induced anxiety- and depression-like behaviors and impaired hippocampus-dependent spatial memory; these effects were mitigated by fludarabin.

Conclusions

IFN-γ primes microglia by activating STAT1, which upregulates genes that activate the NLRP3 inflammasome. Inhibiting the IFN-γ/STAT1 axis may be a way to treat neurodegenerative diseases and psychiatric disorders that involve microglial priming.

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IFN-γ 对小胶质细胞的引诱作用涉及 STAT1 介导的 NLRP3 炎性体的激活。

背景：导致各种神经精神疾病的脑部炎症和免疫反应可能始于小胶质细胞 "启动"。已知干扰素（IFN）-γ可导致小胶质细胞 "启动"，但其机制尚不清楚：我们研究了 IFN-γ 对原代小胶质细胞和小鼠大脑中基因表达、小胶质细胞活化、炎症和免疫反应以及 NLRP3 炎性体活性的影响：结果表明：用 IFN-γ 处理小胶质细胞培养物会诱导刺猬样形态，上调小胶质细胞活化标志物（CD86、CD11b）和促炎分子（IL-1β、IL-6、TNF-α、iNOS），同时下调小胶质细胞稳态标志物（CX3CR1、CD200R1）、抗炎分子（MCR1、Arg-1）和神经营养因子（IGF-1、BDNF）。IFN-γ 还能上调 NLRP3 炎症小体激活的标志物（NLRP3、caspase-1、gasdermin D、IL-18）。这种特殊的转录谱分析使 IFN-γ 激发的小胶质细胞在受到脂多糖（LPS）刺激时反应剧烈。在同时接受 IFN-γ 和 LPS 处理的小胶质细胞培养物中，NLRP3、caspase-1、gasdermin D、IL-1β、IL-18、TNF-α 和 iNOS 的水平均高于单独接受其中一种处理的水平。向小鼠侧脑室注射 IFN-γ 可诱导海马小胶质细胞发生与原代小胶质细胞培养物相似的形态和功能变化。当使用氟达拉滨抑制 STAT1 时，IFN-γ 对 NLRP3 炎性体和培养物或海马小胶质细胞的影响就会消失。给小鼠单独注射 IFN-γ 或同时注射 LPS 会诱发焦虑和抑郁样行为，并损害海马依赖性空间记忆；氟达拉滨可减轻这些影响：结论：IFN-γ 通过激活 STAT1 来激发小胶质细胞，而 STAT1 会上调激活 NLRP3 炎性体的基因。抑制 IFN-γ/STAT1 轴可能是治疗涉及小胶质细胞启动的神经退行性疾病和精神疾病的一种方法。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

CNS Neuroscience & Therapeutics 医学-神经科学

CiteScore

7.30

自引率

12.70%

发文量

240

审稿时长

2 months

期刊介绍： CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.