Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers.
Oral N-acetylcysteine decreases IFN-γ production and ameliorates ischemia-reperfusion injury in steatotic livers.
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DOI：
10.3389/fimmu.2022.898799
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发表时间：
2022
影响因子：
7.3
通讯作者：
Kroemer, Alexander
中科院分区：
文献类型：
--
作者：
Liggett, Jedson R.;Kang, Jiman;Ranjit, Suman;Rodriguez, Olga;Loh, Katrina;Patil, Digvijay;Cui, Yuki;Duttargi, Anju;Nguyen, Sang;He, Britney;Lee, Yichien;Oza, Kesha;Frank, Brett S.;Kwon, DongHyang;Li, Heng-Hong;Kallakury, Bhaskar;Libby, Andrew;Levi, Moshe;Robson, Simon C.;Fishbein, Thomas M.;Cui, Wanxing;Albanese, Chris;Khan, Khalid;Kroemer, Alexander
关键词：
1型自然杀伤T细胞（NKT 1细胞）在介导肝脏缺血再灌注损伤（IRI）中起关键作用。虽然肝脂肪变性是保存型损伤的主要危险因素，但NKT细胞如何影响这一点尚未得到充分研究。鉴于NKT 1细胞被CD 1d识别的磷脂配体激活，我们假设NKT 1细胞是肝IRI的关键调节剂，因为在肝脂肪变性的背景下激活配体的频率增加。我们首先证明，IRI加剧了高脂肪饮食（HFD）在实验性小鼠模型的热局部缺血。这在糖酵解应激的ALT水平和相位器荧光寿命（Phasor-FLIM）成像评价中是明显的。多色流式细胞术发现，与正常饮食（ND）喂养的小鼠相比，HFD喂养的小鼠中CD 45 + CD 3 +NK1.1+ NKT 1细胞显著增加。该观察结果进一步扩展到IRI，测量HFD和ND中的离体细胞因子表达。在IRI后的HFD小鼠中注意到高得多的干扰素-γ（IFN-γ）表达。我们通过对肝组织进行脂质组学分析进一步测试了我们的假设，并将其与使用“长寿命物质”（脂质氧化的副产物）的Phasor-FLIM成像进行了比较。在HFD小鼠中存在较高水平的三酰甘油和磷脂。由于N-乙酰半胱氨酸（NAC）能够限制肝脏脂肪变性，我们测试了HFD小鼠中口服NAC补充剂如何影响IRI。有趣的是，与HFD对照小鼠相比，HFD小鼠中口服NAC补充导致使用对比增强磁共振成像（MRI）的肝脏增强改善，以及通过Phasor-FLIM成像证明的糖酵解正常化。这与血清生化水平的改善以及组织水平和CD 45 + CD 3 + CD 1d+细胞的IFN-γ表达降低相关。在HFD+NAC小鼠中的组织的脂质组学评价显示三酰甘油急剧减少，表明PPAR-γ途径的下调。
Type 1 Natural Killer T-cells (NKT1 cells) play a critical role in mediating hepatic ischemia-reperfusion injury (IRI). Although hepatic steatosis is a major risk factor for preservation type injury, how NKT cells impact this is understudied. Given NKT1 cell activation by phospholipid ligands recognized presented by CD1d, we hypothesized that NKT1 cells are key modulators of hepatic IRI because of the increased frequency of activating ligands in the setting of hepatic steatosis. We first demonstrate that IRI is exacerbated by a high-fat diet (HFD) in experimental murine models of warm partial ischemia. This is evident in the evaluation of ALT levels and Phasor-Fluorescence Lifetime (Phasor-FLIM) Imaging for glycolytic stress. Polychromatic flow cytometry identified pronounced increases in CD45+CD3+NK1.1+NKT1 cells in HFD fed mice when compared to mice fed a normal diet (ND). This observation is further extended to IRI, measuring ex vivo cytokine expression in the HFD and ND. Much higher interferon-gamma (IFN-γ) expression is noted in the HFD mice after IRI. We further tested our hypothesis by performing a lipidomic analysis of hepatic tissue and compared this to Phasor-FLIM imaging using “long lifetime species”, a byproduct of lipid oxidation. There are higher levels of triacylglycerols and phospholipids in HFD mice. Since N-acetylcysteine (NAC) is able to limit hepatic steatosis, we tested how oral NAC supplementation in HFD mice impacted IRI. Interestingly, oral NAC supplementation in HFD mice results in improved hepatic enhancement using contrast-enhanced magnetic resonance imaging (MRI) compared to HFD control mice and normalization of glycolysis demonstrated by Phasor-FLIM imaging. This correlated with improved biochemical serum levels and a decrease in IFN-γ expression at a tissue level and from CD45+CD3+CD1d+ cells. Lipidomic evaluation of tissue in the HFD+NAC mice demonstrated a drastic decrease in triacylglycerol, suggesting downregulation of the PPAR-γ pathway.
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影响因子：
3.6
作者：
Baker SB;Cohen M;Kuo L;Johnson M;Al-Attar A;Zukowska Z
通讯作者：
Zukowska Z
影响因子：
7.3
作者：
Kang, Jiman;Liggett, Jedson R.;Patil, Digvijay;Ranjit, Suman;Loh, Katrina;Duttargi, Anju;Cui, Yuki;Oza, Kesha;Frank, Brett S.;Kwon, DongHyang;Kallakury, Bhaskar;Robson, Simon C.;Fishbein, Thomas M.;Cui, Wanxing;Khan, Khalid;Kroemer, Alexander
通讯作者：
Kroemer, Alexander
DOI：
10.1152/ajprenal.00252.2020
发表时间：
2021-05-01
影响因子：
4.2
作者：
An, Jung Nam;Ryu, Seungwon;Yang, Seung Hee
通讯作者：
Yang, Seung Hee
影响因子：
2.8
作者：
Guimaraes, Alexander R.;Siqueira, Luiz;Caravan, Peter
通讯作者：
Caravan, Peter
DOI：
10.1152/ajpendo.00347.2013
发表时间：
2014-01-01
影响因子：
5.1
作者：
Burke, Susan J.;Lu, Danhong;Collier, J. Jason
通讯作者：
Collier, J. Jason