The receptor tyrosine kinase EphB2 promotes hepatic fibrosis in mice.

Abstract

UNLABELLED:

Beyond the well-defined role of the Eph (erythropoietin-producing hepatocellular) receptor tyrosine kinases in developmental processes, cell motility, cell trafficking/adhesion, and cancer, nothing is known about their involvement in liver pathologies. During blood-stage rodent malaria infection we have found that EphB2 transcripts and proteins were up-regulated in the liver, a result likely driven by elevated surface expression on immune cells including macrophages. This was significant for malaria pathogenesis because EphB2(-/-) mice were protected from malaria-induced liver fibrosis despite having a similar liver parasite burden compared with littermate control mice. This protection was correlated with a defect in the inflammatory potential of hepatocytes from EphB2(-/-) mice resulting in a reduction in adhesion molecules, chemokine/chemokine receptor RNA levels, and infiltration of leukocytes including macrophages/Kupffer cells, which mediate liver fibrosis during rodent malaria infections. These observations are recapitulated in the well-established carbon tetrachloride model of liver fibrosis in which EphB2(-/-) carbon tetrachloride-treated mice showed a significant reduction of liver fibrosis compared to carbon tetrachloride-treated littermate mice. Depletion of macrophages by clodronate-liposomes abrogates liver EphB2 messenger RNA and protein up-regulation and fibrosis in malaria-infected mice.

CONCLUSION:

During rodent malaria, EphB2 expression promotes malaria-associated liver fibrosis; to our knowledge, our data are the first to implicate the EphB family of receptor tyrosine kinases in liver fibrosis or in the pathogenesis of malaria infection.

• Authors: Patrice N Mimche, Lauren M Brady, Christian F Bray, Choon M Lee, Manoj Thapa, Thayer P King, Kendra Quicke, Courtney D McDermott, Sylvie M Mimche, Arash Grakoui, Edward T Morgan, Tracey J Lamb
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 62 Issue 3 Pg. 900-14 (Sep 2015) ISSN: 1527-3350 [Electronic] United States
• PMID: 25784101 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2015 by the American Association for the Study of Liver Diseases.

Chemical References

• Receptors, Chemokine
• Receptor, EphB2

Topics

• Animals
• Cell Movement (immunology, physiology)
• Cell Survival
• Cells, Cultured
• Disease Models, Animal
• Disease Progression
• Female
• Hepatocytes (enzymology, metabolism)
• Kupffer Cells (metabolism)
• Liver Cirrhosis (enzymology, pathology)
• Macrophages (metabolism)
• Malaria (pathology, physiopathology)
• Mice
• Mice, Inbred C57BL
• Receptor, EphB2 (metabolism)
• Receptors, Chemokine (metabolism)
• Up-Regulation