Activation of Invariant Natural Killer T Cells Enhances Ischemia-Reperfusion Injury in Steatotic Mouse Livers

Hepatic steatosis is a significant independent risk factor for liver surgery because of its vulnerability to ischemia-reperfusion (IR) injury. Invariant natural killer T (iNKT) cells contribute to IR injury in healthy liver. We previously reported that activated iNKT cells mitigate liver IR injury and facilitate liver repair by interacting with macrophages. This study aimed to assess the role of activated iNKT cells in IR injury in steatotic livers.

Male C57/BL6 mice were fed a normal diet (ND) or high-fat diet (HFD) for 12 weeks before liver IR. iNKT cells were activated by intraperitoneal injection of α-galactosylceramide (α-GC) into HFD-fed mice. This study assessed liver injury, cytokine levels, and immune cell accumulation.

HFD-fed mice exhibited increased levels of liver injury, pro-inflammatory mediators, and macrophages compared to those of ND-fed mice. Administration of α-GC to HFD-fed mice enhanced liver IR injury that was associated with increased numbers of iNKT cells and pro-inflammatory macrophages compared with those in the vehicle-treated group. Additionally, liver repair was delayed in α-GC-treated HFD-fed mice, as demonstrated by the increased necrotic area and decreased proliferating cell nuclear antigen expression. This was accompanied by reduced levels of anti-inflammatory mediators and reparative macrophages. Pro-inflammatory cytokine levels were increased in activated hepatic iNKT cells co-cultured with macrophages isolated from HFD-fed mice.

The activation of hepatic iNKT cells aggravates steatotic liver IR injury by upregulating pro-inflammatory mediators and macrophages, while suppressing anti-inflammatory mediators and reparative macrophages.