阻断 ATGL 介导的小胶质细胞脂滴分解可减轻对脂多糖的神经炎症反应和行为反应

IF 8.8 2区 医学 Q1 IMMUNOLOGY Brain, Behavior, and Immunity Pub Date : 2024-09-24 DOI:10.1016/j.bbi.2024.09.027
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引用次数: 0

摘要

脂滴(LD)是储存甘油三酯的细胞器,已成为细胞炎症反应的重要组成部分。脂滴通过脂肪甘油三酯脂肪酶(ATGL)(一种催化甘油三酯脂肪分解限速步骤的酶)进行脂肪分解,从而调节外周免疫细胞和非免疫细胞的炎症反应。ATGL 以细胞类型依赖的方式在外周引起促炎和抗炎反应。本研究确定了抑制 ATGL 和小胶质细胞特异性 ATGL 基因功能缺失对急性炎症反应和对促炎症损伤的行为反应的影响。首先,我们评估了脂肪分解抑制对小鼠原代小胶质细胞培养物中脂多糖(LPS)诱导的细胞因子表达和分泌以及吞噬作用的影响。脂肪酶抑制剂(ORlistat 和 ATGListatin)和 LPS 会导致 LD 在小胶质细胞中积累。用ORlistat抑制泛脂肪酶可减轻LPS诱导的IL-1β和IL-6的表达。在新生儿和成年小胶质细胞培养物中,特异性抑制 ATGL 对 CCL2、IL-1β 和 IL-6 的表达也有类似作用。ATGListatin 或敲除 ATGL 也会减少 CCL2 和 IL-6 的分泌。ATGListatin 增加了新生儿培养物的吞噬能力,而与 LPS 处理无关。其次,靶向和非靶向脂质分析表明,ATGListatin 可减少 LPS 诱导的促炎前列腺素的生成,并调节新生小胶质细胞中的神经酰胺种类。最后,我们使用一种新型小胶质细胞特异性和诱导性 ATGL 基因敲除小鼠模型评估了小胶质细胞 ATGL 在神经炎症中的作用。成年雄性小鼠小胶质细胞 ATGL 的缺失抑制了 LPS 诱导的 IL-6 和 IL-1β 的表达以及小胶质细胞的密度。在小胶质细胞 ATGL 缺失的雄性小鼠中,LPS 诱导的病态和焦虑行为也有所减少。总之,我们的研究结果表明,通过药物或基因抑制 ATGL 介导的甘油三酯脂解作用可产生强大的抗炎效果,从而提出抑制小胶质细胞 LD 脂解作用对急性神经炎症有益处。
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Blockage of ATGL-mediated breakdown of lipid droplets in microglia alleviates neuroinflammatory and behavioural responses to lipopolysaccharides
Lipid droplets (LD) are triglyceride storing organelles that have emerged as an important component of cellular inflammatory responses. LD lipolysis via adipose triglyceride lipase (ATGL), the enzyme that catalyses the rate-limiting step of triglyceride lipolysis, regulates inflammation in peripheral immune and non-immune cells. ATGL elicits both pro- and anti-inflammatory responses in the periphery in a cell-type dependent manner. The present study determined the impact of ATGL inhibition and microglia-specific ATGL genetic loss-of-function on acute inflammatory and behavioural responses to pro-inflammatory insult. First, we evaluated the impact of lipolysis inhibition on lipopolysaccharide (LPS)-induced expression and secretion of cytokines and phagocytosis in mouse primary microglia cultures. Lipase inhibitors (ORlistat and ATGListatin) and LPS led to LD accumulation in microglia. Pan-lipase inhibition with ORlistat alleviated LPS-induced expression of IL-1β and IL-6. Specific inhibition of ATGL had a similar action on CCL2, IL-1β and IL-6 expression in both neonatal and adult microglia cultures. CCL2 and IL-6 secretion were also reduced by ATGListatin or knockdown of ATGL. ATGListatin increased phagocytosis in neonatal cultures independently from LPS treatment. Second, targeted and untargeted lipid profiling revealed that ATGListatin reduced LPS-induced generation of pro-inflammatory prostanoids and modulated ceramide species in neonatal microglia. Finally, the role of microglial ATGL in neuroinflammation was assessed using a novel microglia-specific and inducible ATGL knockout mouse model. Loss of microglial ATGL in adult male mice dampened LPS-induced expression of IL-6 and IL-1β and microglial density. LPS-induced sickness- and anxiety-like behaviours were also reduced in male mice with loss of ATGL in microglia. Together, our results demonstrate potent anti-inflammatory effects produced by pharmacological or genetic inhibition of ATGL-mediated triglyceride lipolysis and thereby propose that supressing microglial LD lipolysis has beneficial actions in acute neuroinflammatory conditions.
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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.
期刊最新文献
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