Dataset Information

Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.

ABSTRACT: 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-? 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 J?18^-/- 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.

SUBMITTER: Wang H

PROVIDER: S-EPMC7797696 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.

Wang Haitao H Li Longjun L Li Yinling Y Li Yue Y Sha Yeqin Y Wen Shuang S You Qiang Q Liu Lixin L Shi Meiqing M Zhou Hong H

Theranostics 20210101 5

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 ...[more]

PMID: 33500717

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Project description:A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.

Dataset Information

Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.

Publications

Intravital imaging of interactions between iNKT and kupffer cells to clear free lipids during steatohepatitis.

Similar Datasets

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