CXCR3+ hepatic natural killer cells promote hepatic ischemia-reperfusion injury in liver transplantation

Abstract

<p><strong>Background</strong> Liver ischemia-reperfusion injury (IRI) refers to the interruption of liver blood supply upon reperfusion, which rapidly leads to liver damage in an antigen-independent way. Almost 50% of all intrahepatic lymphocytes are NK cells, constituted by liver-infiltrated and liver-resident NK cells, that play key roles in the immune response against pathological conditions. However, the role of hepatic NK (he-NK) cells in liver IRI is controversial.</p><p><strong>Methods</strong> The correlations among the number of he-NK cells, liver function, and inflammatory cytokines were analyzed in the local human LT cohort. Mouse IRI model with the administration of anti-NK cell antibodies (anti-ASGM1 or anti-NK1.1) was applied to investigate the role of TLR4/CXCL10/CXCR3 on the mobilization of he-NK cells.</p><p><strong>Results</strong> The number of intra-graft NK cells was significantly increased at 2 hours post-reperfusion compared to normal livers, with an increase in inflammatory signatures of circulating cytokines (IL-2, IL-6, IFN-γ, CXCL10) and ALT levels. In the mouse model, the number of peripheral NK cells and he-NK cells were not significantly changed after hepatic IRI, but the number of liver-infiltrated NK cells was significantly increased in the IRI lobe. There were remarkable increases in CXCR3 expression on both liver-resident and liver-infiltrated NK cells. Anti-NK1.1 antibodies can deplete whole he-NK cells, while anti-ASGM1 antibodies can only suppress the liver-infiltrated NK cells. Notably, the liver function was preserved in both groups compared to negative controls but was better in the anti-NK1.1 group than in the anti-ASGM1 one, indicating both liver-resident and liver-infiltrated NK cells promoted hepatic IRI. In the CXCR3 knockout mice, the differences in ALT levels between the anti-NK1.1 and anti-ASGM1 groups were not observed after hepatic IRI. The knockout of TLR4 or CXCL10 significantly protected liver function by decreasing CXCR3+ he-NK cells.</p><p><strong>Conclusions</strong> Both liver-resident and liver-infiltrated NK cells medicated hepatic IRI in a CXCR3-dependent manner, regulated by upstream TLR4/CXCL10 signaling.</p>