Endothelial YAP/TEAD1-CXCL17 signaling recruits myeloid-derived suppressor cells against liver ischemia-reperfusion injury.

Abstract

Liver ischemia-reperfusion injury (IRI) is a common complication of liver transplantation and hepatectomy, and causes acute liver dysfunction and even organ failure. Myeloid-derived suppressor cells (MDSCs) accumulate and play immunosuppressive function in cancers and inflammation. However, the role of MDSCs in liver IRI has not been defined. We enrolled recipients receiving orthotopic liver transplantation (OLT) and obtained the pre-OLT/post-OLT blood and liver samples. The proportions of MDSCs were significantly elevated after OLT and negatively associated with liver damage. In single-cell RNA-sequencing analysis of liver samples during OLT, two cell clusters with MDSC-like phenotypes were identified and showed maturation and infiltration in post-OLT livers. In mice model, liver IRI mobilized MDSCs and promoted their infiltration in damaged liver, and intrahepatic MDSCs possessed with enhanced immunosuppressive function by up-regulation of STAT3 signaling. Under treatment with αGr-1 antibody or adoptive transfer MDSCs to change the proportion of MDSCs in vivo, we found that intrahepatic MDSCs alleviated liver IRI-induced inflammation and damage by inhibiting M1 macrophage polarization. Mechanistically, bulk RNA-sequencing analysis and in vivo experiments verified that CXCL17 was upregulated by YAP/TEAD1 signaling and subsequently recruited MDSCs via binding with GPR35 during liver IRI. Moreover, hepatic endothelial cells were the major cells responsible for CXCL17 expression in injured livers, among which hypoxia-reoxygenation stimulation activated YAP/TEAD1 complex to promote CXCL17 transcription. Endothelial YAP/TEAD1-CXCL17 signaling recruited MDSCs to attenuate liver IRI, providing evidence of a therapeutic potential for managing IRI in liver surgery.