Fiorelle Aguilar

Lytic cell death pathways drive hepatic ischemia-reperfusion injury (IRI). The transmembrane protein ninjurin-1 (NINJ1) aggregates in the plasma membrane to permeabilize the cell during multiple cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1 mediates liver IRI and that its inhibition would mitigate injury. We found that NINJ1 is highly expressed in human liver tissue and that its up-regulation and activation correlate with early allograft dysfunction in liver transplant patients. Using a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. We therefore position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for liver transplantation.

Hepatic ischemia-reperfusion injury (IRI) results from interrupted perfusion to the liver and contributes to acute liver dysfunction such as following liver transplantation. Lytic cell death pathways are major drivers of IRI and the subsequent inflammatory response. The transmembrane protein ninjurin-1 (NINJ1) was identified as the key executor of terminal plasma membrane rupture across multiple lytic cell death pathways implicated in hepatic IRI. We hypothesized that NINJ1-mediated lytic cell death drives IRI and that its therapeutic inhibition would mitigate liver IRI. Using human liver specimens, we found that NINJ1 is highly expressed in human liver tissue and that its activation correlates with early allograft dysfunction in patients undergoing liver transplantation. Utilizing a segmental hepatic IRI model in mice and rats, Ninj1 genetic deletion or pharmacologic inhibition diminished acute liver injury. Mice with hepatocyte- or macrophage-specific Ninj1 knockout both had reduced hepatocellular injury following IRI, suggesting that NINJ1 within both populations contributes to the resulting liver injury. Mechanistically, we found that hepatocytes and Kupffer cells are highly susceptible to hypoxia-induced NINJ1-mediated plasma membrane rupture, which can be pharmacologically prevented. These data position NINJ1 as a potential new therapeutic target to limit hepatic IRI, with important implications for organ preservation during liver transplantation.