Loss of L-selectin-guided CD8 , but not CD4 , cells protects against ischemia reperfusion injury in a steatotic liver.

UNLABELLED

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 nonexistent. The objective of the current study was to delineate the contribution of specific phenotypes of T cells and adhesion molecules in exacerbated cell death in steatotic liver injury. 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. Cluster of differentiation 8 knockout (CD8 ) and CD4 mice along with CD8 and L-selectin antibody-treated mice were fed an HFD, and hepatocellular injury was assessed by histology, propidium iodide injection, and alanine aminotransferase after IRI. RNA sequencing demonstrated a strikingly differential gene profile in steatotic hepatocytes versus lean hepatocytes. After injury, the HFD liver showed increased necrosis, infiltrating CD8 cells, alanine aminotransferase, 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 therapeutic target in steatotic liver injury, underlining the importance of development of therapies specific to a steatotic liver. (Hepatology 2017;66:1258-1274).