Targeting Innate Immune Cells and Regulated Cell Death in Early Hepatic Ischemia Reperfusion Injury

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Abstract

Background

Ischemia reperfusion injury (IRI) remains an important problem in clinical organ transplantation. Regulated cell death (RCD) events like ferroptosis and necroptosis are involved and there is growing evidence that innate unconventional effector T cells, namely γδ T cells play a key role in mediating early hepatic IRI. However, the mechanisms underlying the T cell-RCD crosstalk are poorly understood. In this study, we target RCD pathways and investigate the effect on early γδ T cell activation.

Methods

We investigate early immunological events in a well-established model of hepatic IRI in wild-type mice, where we blocked RCD (ferroptosis) enzymes by novel inhibitors. Treated and untreated mice underwent a 90 min partial warm ischemia, followed by 24 hours of reperfusion. Furthermore, we used genetically modified mice where RCD regulators where knocked out as controls. Hepatocellular injury was evaluated by HE-histology and serum-transaminase measurement. Hepatic leukocyte subsets, e.g. innate effector cell populations and cytokine secretion were characterized by immunohistochemistry, ELISA, RT-PCR and polychromatic FACS.

Results

Mice treated with ferroptosis inhibitor (or mice deficient for a key ferroptosis regulator) were protected from hepatic IRI (e.g. serum transaminase levels 920U/l vs. 2540U/l in wt controls; p=0.02). We found that unconventional CD27-γδTCR+ and CD4-CD8- double-negative (DN) T cells, which are the major effector cells in hepatic IRI, are significantly reduced in the livers of those mice, where the RCD pathway is blocked (either genetically or by drugs). We further show that the proinflammatory cytokine TNFα, which can induce further necroptosis events, is reduced in these KO animals.

Conclusion

Ferroptosis events appear to be the initial activator for hepatic IRI and lead to further progression by activating innate unconventional CD27-γδTCR+ and CD4-CD8- double-negative (DN) T cells. This opens new therapeutic options to improve LTx outcomes.

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