First Author | Kolachala VL | Year | 2017 |
Journal | Hepatology | Volume | 66 |
Issue | 4 | Pages | 1258-1274 |
PubMed ID | 28543181 | Mgi Jnum | J:313227 |
Mgi Id | MGI:6791701 | Doi | 10.1002/hep.29276 |
Citation | Kolachala VL, et al. (2017) Loss of L-selectin-guided CD8(+) , but not CD4(+) , cells protects against ischemia reperfusion injury in a steatotic liver. Hepatology 66(4):1258-1274 |
abstractText | 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). |