Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway.
Intermittent fasting reduces neuroinflammation in intracerebral hemorrhage through the Sirt3/Nrf2/HO-1 pathway.
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间歇性禁食通过 Sirt3/Nrf2/HO-1 通路减少脑出血中的神经炎症
DOI：
10.1186/s12974-022-02474-2
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发表时间：
2022-05-27
影响因子：
9.3
通讯作者：
中科院分区：
文献类型：
--
作者：
炎症反应导致脑出血预后不良。间歇性禁食（IF）已被证明在多种致病过程中对炎症具有保护作用。在本研究中，我们的目的是调查的有益影响，在减轻神经炎症和神经功能缺损的小鼠模型，脑出血，并探讨其潜在的机制。在雄性对照小鼠（C57 BL/6）、小胶质细胞特异性敲除Sirt 3f/f的小鼠中，通过纹状体内注射自体血液来模拟ICH，通过每隔一天喂食来模拟IF; Cx 3cr 1-Cre（Sirt 3 cKO）和Sirt 3f/f（野生型）小鼠。分别于脑出血后1、3、7、28 d取脑组织和动脉血，进行Iba-1、DARPP-32和HO-1的免疫组化分析，HE染色进行形态学分析，ELISA法进行炎性因子释放试验。神经功能测定采用角隅试验和圆柱试验。Iba-1与CD 16、Arg 1或Sirt 3的荧光双标记染色用于提供这些分子在小胶质细胞中共表达的直接图像。TUNEL、切割的caspase-3和Nissl染色以评估细胞损伤。IF可减轻脑出血后急性期和慢性期的神经功能缺损。形态学上，IF可促进急性期血肿清除，减轻脑水肿，减轻慢性期纹状体萎缩。另外，IF还能减少脑出血后第1、3、7天TUNEL阳性细胞数，增加Nissl阳性神经元数。IF抑制ICH后第3天的CD 16 +Iba-1+小胶质细胞活化，并减少炎症释放，如IL-1β和TNF-α。小胶质细胞Sirt 3基因的缺失可减弱IF的上述作用，部分原因是抑制了Nrf 2/HO-1信号通路。有趣的是，IF在第7天增加主要表达Arg 1的Iba-1+小胶质细胞数量，同时降低促炎因子水平。在小胶质细胞特异性Sirt 3缺失的小鼠中，与野生型Sirt 3f/f小鼠相比，IF对Iba-1+小胶质细胞活化和抗炎因子表达的影响减弱。IF通过Sirt 3/Nrf 2/HO-1通路抑制炎症反应来预防ICH。在线版本包含补充材料，可通过10.1186/s12974-022-02474-2获得。
Inflammation contributes to the poor prognosis of intracerebral hemorrhage (ICH). Intermittent fasting (IF) has been shown to be protective against inflammation in multiple pathogenic processes. In the present study, we aimed to investigated the beneficial effects of IF in attenuating neuroinflammation and neurological deficits in a mouse model of ICH and to investigate the underlying mechanism. ICH was modeled by intrastriatal injection of autologous blood and IF was modeled by every-other-day feeding in male control mice (C57BL/6), mice with and microglia specific knockout Sirt3f/f;Cx3cr1-Cre (Sirt3 cKO), and Sirt3f/f (wild-type) mice. Brain tissues and arterial blood were harvested at 1, 3, 7 and 28 days after ICH for immunohistochemistry analysis of Iba-1, DARPP-32 and HO-1, morphological analysis by HE staining and inflammatory factor release tests by ELISA. Neurological functions were approached by corner test and cylinder test. Fluorescent double-labeled staining of Iba-1 with CD16, Arg1 or Sirt3 was used to provide direct image of co-expression of these molecules in microglia. TUNEL, cleaved caspase-3 and Nissl staining was performed to evaluate cellular injuries. IF alleviated neurological deficits in both acute and chronic phases after ICH. Morphologically, IF enhanced hematoma clearance, reduced brain edema in acute phase and attenuated striatum atrophy in chronic phase. In addition, IF decreased the numbers of TUNEL+ cells and increased Nissl+ neuron number at day 1, 3 and 7 after ICH. IF suppressed CD16+Iba-1+ microglia activation at day 3 after ICH and reduced inflammatory releases, such as IL-1β and TNF-α. The above effects of IF were attenuated by microglia Sirt3 deletion partly because of an inhibition of Nrf2/HO-1 signaling pathway. Interestingly, IF increased Iba-1+ microglia number at day 7 which mainly expressed Arg1 while decreased the proinflammatory factor levels. In mice with microglia-specific Sirt3 deletion, the effects of IF on Iba-1+ microglia activation and anti-inflammatory factor expressions were attenuated when compared with wild-type Sirt3f/f mice. IF protects against ICH by suppressing the inflammatory responses via the Sirt3/Nrf2/HO-1 pathway. The online version contains supplementary material available at 10.1186/s12974-022-02474-2.
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