*Purpose: Liver ischemia-reperfusion injury (IRI) is recognized as an innate immunity-driven local inflammation response during hemorrhagic shock, liver resection and transplantation. Yes-associate protein 1 (YAP) is the major downstream effector of hippo pathway.

*Methods: This study evaluated the pivotal role of myeloid YAP signaling in a murine model of liver warm IRI.

*Results: In our previous study, we found that YAP expression was triggered in human orthotopic liver transplantation (OLT). High post-OLT YAP expression was correlated with well-preserved histology and improved hepatocellular function at post-operative day 1-7. In a mouse model of liver warm ischemia (90min) followed by reperfusion (0-24h), YAP was readily triggered in WT mice after the ischemia insult. Interestingly, unlike in flox control mates, IR stress exacerbated significant liver damage in myeloid YAP deficient mice (YAP^M-KO), as evidenced by elevated serum alanine aminotransferase (sALT) level and damaged hepatic architecture. Myeloid YAP deficiency promoted liver IRI deteriorated liver pathology (more severe lobular edema, widespread hemorrhage, and congestion/hepatocellular necrosis), and enhanced hepatic ROS accumulation. On the other hand, compared with YAP-proficient (YAP^FL/FL) mice, Myeloid specific YAP deficiency exacerbated innate immune responses, as shown by amplified CD68+ macrophages and Ly6G+ neutrophils sequestration in liver IR-livers, and enhanced pro-inflammatory cytokine profile (TNF-α, IL-1β, IFN-β, and CXCL-10).

*Conclusions: Our novel findings document the critical role of myeloid YAP signaling in hepatic homeostasis and cytoprotection in liver IRI. Because the enhancement of YAP signaling differentially regulates local innate inflammation and hepatocyte survival, these results provide the rationale for emerging approaches to manage liver IRI in transplant patients.

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