1. Academic Validation
  2. Invariant natural killer T cells drive hepatic homeostasis in nonalcoholic fatty liver disease via sustained IL-10 expression in CD170+ Kupffer cells

Invariant natural killer T cells drive hepatic homeostasis in nonalcoholic fatty liver disease via sustained IL-10 expression in CD170+ Kupffer cells

  • Eur J Immunol. 2023 Jul 25;e2350474. doi: 10.1002/eji.202350474.
Mutian Han # 1 Jinke Geng # 1 Shuangshuang Zhang 1 Jia Rao 1 Yansong Zhu 2 Shaodong Xu 2 Fei Wang 1 Fang Ma 3 Meng Zhou 2 Hong Zhou 1 2
Affiliations

Affiliations

  • 1 Department of Immunology, College of Basic Medical Science, Anhui Medical University, Anhui, China.
  • 2 Department of Cell and Biology, College of Life Sciences, Anhui Medical University, Anhui, China.
  • 3 Center for Scientific Research, Anhui Medical University, Anhui, China.
  • # Contributed equally.
Abstract

Kupffer cells (KCs) are liver-resident macrophages involved in hepatic inflammatory responses, including nonalcoholic fatty liver disease (NAFLD) development. However, the contribution of KC subsets to liver inflammation remains unclear. Here, using high-dimensional single-cell RNA Sequencing, we characterized murine embryo-derived KCs and identified two KC populations with different gene expression profiles: KC-1 and KC-2. KC-1 expressed CD170, exhibiting immunoreactivity and immune-regulatory abilities, while KC-2 highly expressed lipid metabolism-associated genes. In a high-fat diet-induced NAFLD model, KC-1 cells differentiated into pro-inflammatory phenotypes and initiated more frequent communications with invariant natural killer T (iNKT) cells. In KC-1, interleukin (IL)-10 expression was unaffected by the high-fat diet but impaired by iNKT cell ablation and upregulated by iNKT cell adoptive transfer in vivo. Moreover, in a cellular co-culture system, primary hepatic iNKT cells promoted IL-10 expression in RAW264.7 and primary KC-1 cells. CD206 signal blocking in KC-1 or CD206 knockdown in RAW264.7 cells significantly reduced IL-10 expression. In conclusion, we identified two embryo-derived KC subpopulations with distinct transcriptional profiles. The CD206-mediated crosstalk between iNKT and KC-1 cells maintains IL-10 expression in KC-1 cells, affecting hepatic immune balance. Therefore, KC-based therapeutic strategies must consider cellular heterogeneity and the local immune microenvironment for enhanced specificity and efficiency.

Keywords

Immune homeostasis; Invariant natural killer T cells; Kupffer cells; Nonalcoholic fatty liver disease.

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