Role of NK cells in hepatic ischemia/reperfusion injury in mice

Introduction: The liver is the primary organ affected by ischemia/reperfusion injury (IRI) after shock, surgical resection, or transplantation. In this context, myeloid leukocytes as well as T cells have been intensively studied, as they are thought to be primarily propagating the injury response. Interestingly, recent evidence implies NK cells in the pathogenesis of IRI as well. Nevertheless, the precise role of NK cells in IRI still remains enigmatic and clearly warrants further investigation.

Methods: Wild-type (wt) C57BL/6, B6.Rag and Rag-common-γ-chain (Rag-γc) double-KO mice were subjected to 60 min of partial hepatic ischemia. For this, midline laparotomy was performed and the blood supply to the left and median lobes of the liver was interrupted via atraumatic clipping. Hepatic reperfusion was initiated 60 min later. Control animals underwent sham surgery. After 6 and 24h, animals were sacrificed for further functional, histological, and flowcytometric analyses.

Results: Importantly, we found that hepatic IRI, as measured by serum ALT levels, was attenuated in Rag and Rag-γc KO mice after 6 and 24h, when compared to wt B6 mice. This was further corroborated by histological analyses from ischemic liver lobe sections from Rag and Rag-γc KO vs. wt B6 mice, as shown by levels of hepatocellular necrosis. Most interestingly, polychromatic flowcytometry demonstrated that CD27- NK cells pre-dominatingly infiltrated ischemic liver lobes in wt B6 and Rag KO mice, indicating a potentially pathogenic role of this particular NK subset in IRI.

Discussion: Our study indicates a novel and underestimated role of NK cells in IRl, and may provide first relevant mechanistic insights into the pathogenesis behind. This might be of high relevance for liver surgery, transplantation, and beyond.

NK cells - ischemia reperfusion injury - liver regeneration