Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.
Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.
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脂肪性肝炎期间 iNKT 和库普弗细胞之间相互作用清除游离脂质的活体成像
作者：
Wang H;Li L;Li Y;Li Y;Sha Y;Wen S;You Q;Liu L;Shi M;Zhou H
原理：不变的自然杀伤T（iNKT）细胞和枯否细胞代表先天免疫细胞的主要肝脏群体。然而，它们在脂肪性肝炎中的作用仍然知之甚少。为了阐明它们在脂肪性肝炎发展中的功能，有必要进行实时体内分析，以了解饮食诱导的脂肪性肝炎期间它们之间动态相互作用的病理生理事件。方法：我们采用蛋氨酸胆碱缺乏（MCD）饮食诱导的脂肪性肝炎动物模型。采用多光子共聚焦活体成像技术和常规实验技术，研究脂肪性肝炎中iNKT和Kupffer细胞的病理微环境、它们之间的相互作用以及这些相互作用的生物学效应。结果如下：我们发现，在脂肪性肝炎的早期阶段，iNKT细胞被募集并聚集成小簇，并与枯否细胞动态相互作用。最重要的是，簇中的iNKT细胞清除坏死肝细胞释放的游离脂质，并呈现具有高IFN-γ表达的非经典活化状态。此外，细胞簇中的Kupffer细胞被极化为M1型。iNKT细胞的转录组测序显示与吞噬作用和脂质加工相关的基因上调。将iNKT细胞连续转移至Jα18-/-小鼠表明，iNKT和Kupffer细胞簇对于平衡肝脏和外周脂质水平以及抑制肝纤维化发展至关重要。结论：我们的研究确定了iNKT细胞和枯否细胞之间的动态相互作用在早期脂肪性肝炎期间促进iNKT细胞的脂质吞噬和清除中的重要作用。因此，调节iNKT细胞是早期脂肪性肝炎的潜在治疗策略。
Rationale: Invariant natural killer T (iNKT) cells and Kupffer cells represent major hepatic populations of innate immune cells. However, their roles in steatohepatitis remain poorly understood. To elucidate their functions in steatohepatitis development, real-time, in vivo analysis is necessary to understand the pathophysiological events in the dynamic interactions between them during diet-induced steatohepatitis. Methods: We used a steatohepatitis animal model induced by a methionine-choline-deficient (MCD) diet. Multi-photon confocal live imaging and conventional experimental techniques were employed to investigate the hepatic pathological microenvironment of iNKT and Kupffer cells, interactions between them, and the biological effects of these interactions in steatohepatitis. Results: We found that iNKT cells were recruited and aggregated into small clusters and interacted dynamically with Kupffer cells in the early stage of steatohepatitis. Most significantly, the iNKT cells in the cluster cleared free lipids released by necrotic hepatocytes and presented a non-classical activation state with high IFN-γ expression. Furthermore, the Kupffer cells in the cell cluster were polarized to type M1. The transcriptome sequencing of iNKT cells showed upregulation of genes related to phagocytosis and lipid processing. Adoptive transfer of iNKT cells to Jα18-/- mice showed that iNKT and Kupffer cell clusters were essential for balancing the liver and peripheral lipid levels and inhibiting liver fibrosis development. Conclusions: Our study identified an essential role for dynamic interactions between iNKT cells and Kupffer cells in promoting lipid phagocytosis and clearance by iNKT cells during early liver steatohepatitis. Therefore, modulating iNKT cells is a potential therapeutic strategy for early steatohepatitis.
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影响因子：
9.1
作者：
DiNicolantonio JJ;Lucan SC;O'Keefe JH
通讯作者：
O'Keefe JH
影响因子：
44.1
作者：
Jing D;Zhang S;Luo W;Gao X;Men Y;Ma C;Liu X;Yi Y;Bugde A;Zhou BO;Zhao Z;Yuan Q;Feng JQ;Gao L;Ge WP;Zhao H
通讯作者：
Zhao H
影响因子：
30.5
作者：
Facciotti, Federica;Ramanjaneyulu, Gundimeda S.;De Libero, Gennaro
通讯作者：
De Libero, Gennaro
影响因子：
13.5
作者：
Guebre-Xabier, M;Yang, SQ;Diehl, AM
通讯作者：
Diehl, AM
影响因子：
30.5
作者：
Kinjo, Yuki;Tupin, Emmanuel;Kronenberg, Mitchell
通讯作者：
Kronenberg, Mitchell