Loss of L- Selectin Guided CD8+ but not CD4+ Cells, Protects Against Ischemia Reperfusion Injury in a Steatotic Liver

Abstract

Background & Aims: Steatotic liver responds with increased hepatocellular injury when exposed to an ischemic-reperfusion insult. Increasing evidence supports the role of immune cells as key mediators of this injury in a normal (lean) state, but data about their role in a steatotic liver are practically non-existent. The objective of the current study was to delineate contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. Methods: RNA sequencing was performed on isolated steatotic primary hepatocytes and T cell markers were assessed in hepatic lymphocytes after ischemia reperfusion injury (IRI) in high fat diet (HFD) fed mice. CD8^-/- and CD4^-/- mice along with CD8 and L-selectin antibody treated mice were fed on a HFD and hepatocellular injury was assessed by histology, propidium iodide injection and ALT after IRI. Results: RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes vs. lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8⁺ cells, ALT and proinflammatory cytokines. Hepatic lymphocytes demonstrated increased CD8⁺/CD62L⁺(L-selectin) cells in HFD fed mice after IRI. CD8^-/- mice and CD8 depleted C57BL/6 mice, demonstrated significant protection from injury, which was not seen in CD4^-/- mice. L-selectin blockade also demonstrated significant hepatoprotection from IRI. L selectin ligand MECA-79 was increased in HFD fed mice undergoing IRI. Conclusion: Blockade of CD8 and L-selectin but not CD4, ameliorated hepatocellular injury, confirming that CD8⁺ cells are critical drivers of injury in a steatotic liver. This represents a novel therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. This article is protected by copyright. All rights reserved.

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