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

Abstract

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).

• Authors: Vasantha L Kolachala, Sirish Palle, Ming Shen, Alayna Feng, Dmitry Shayakhmetov, Nitika A Gupta
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 66 Issue 4 Pg. 1258-1274 (10 2017) ISSN: 1527-3350 [Electronic] United States
• PMID: 28543181 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2017 by the American Association for the Study of Liver Diseases.

Chemical References

• Cytokines
• L-Selectin

Topics

• Animals
• CD4-Positive T-Lymphocytes (physiology)
• CD8-Positive T-Lymphocytes (physiology)
• Cytokines (blood)
• Diet, High-Fat
• Fatty Liver (complications)
• L-Selectin (physiology)
• Liver (pathology)
• Male
• Mice, Inbred C57BL
• Reperfusion Injury (blood, immunology, pathology)