Erin Cha

Introduction. In the world, 25% of the population has risk factors for liver disease with over 800,000 deaths from liver cancer.^1,2 Amidst an organ shortage, when liver transplantation is often the only therapy for end-stage liver disease, the need for successful transplants is crucial.^1,2 One of the main causes of graft dysfunction and liver failure post-transplantation is hepatic ischemia-reperfusion injury (IRI).³ This injury involves microcirculatory disorders that not only locally impact the area of ischemia, but also the surrounding tissue resulting in organ failure. In the liver microcirculation, Kupffer cells (KCs) are known to regulate inflammatory responses and their phenotypic changes in association with functional alterations may contribute to the pathogenesis of IRI during transplantation.^3,5 Moreover, the role of KC apoptosis in liver IRI remains unclear. KC apoptosis has been shown to reduce IRI in liver transplantation by reducing overexpression of KCs’ pro-inflammatory factors, but it has also been demonstrated to have a protective effect through the upregulation of anti-inflammatory factors.⁴ The possible cross-talk between KC secreted inflammatory factors and cell death pathways influencing the outcome of IRI also cannot be excluded. Methods. Mice with/without deleted Eva1a, a lysosomal/endoplasmic reticulum-related protein involved in regulating autophagy and apoptosis, were subjected to 90-min ischemia before reperfusion, in which KCs were isolated and levels of inflammatory factors were measured by ELISA at 6 hours post-reperfusion.⁶ Moreover, the specific types of KCs were analyzed after 90-min ischemia and the percentages of KCs/macrophages were assayed at zero and six hours post-reperfusion through FACS analysis.⁷ Mouse livers were also reconstituted with KCs and tissue damage was evaluated through Suzuki scores and sALT.⁷ Results. Eva1a was upregulated in KCs by liver insult and induced KC autophagy, leading to downstream NLPR3 inhibition and decreased IL-β and caspase-1 expressions to limit excessive activation of inflammation and injury.⁶ At 6 hours post-reperfusion, KCs were depleted while infiltrating macrophages were increased, in which reconstitution of KCs reduced liver tissue damage.⁷ Conclusions. The anti-inflammatory role of KCs is crucial for reducing IRI, however, more studies are needed to examine the specific KC/macrophage population at different stages of IRI to identify the effect of KC apoptosis. Additionally, the potential cross-talk between KC secreted factors and other cell death pathways reveals the multifaceted nature of KC apoptosis that can have different downstream effects either attenuating or exacerbating tissue injury. Therefore, approaches to therapeutics must be multifold and the timing of delivery is crucial.

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