Modulating CD4+ T cell migration in the postischemic liver

Background. CD4+ T-cells play a critical role during hepatic ischemia-reperfusion (I/R) injury although the mechanisms of their migration in the post-ischemic liver remain unclear. Recent studies suggest that emigrated T-cells are colocalized with hepatic stellate cells (HSCs) during viral hepatitis. We answered the questions of whether hepatic stellate cells (HSCs) interact with CD4+ T-cells during I/R of the liver and whether modulation of HSC activity affects T-cell-dependent I/R injury. Methods. In mice, migration of CD4+ T-cells was analyzed in vivo using conventional intravital microscopy and two-photon microscopy in sham-operated mice and in mice after I/R (90 min/120min). CD4+ T-cell-HSC interactions were visualized after infusion of fluorescence-labeled CD4+ T-cells into Cx3CR1 mice (mice exhibiting GFP-labeled HSCs) after I/R. Because the activation of HSC is controlled by endocannabinoid receptors, CB-1 and CB-2, the mice received treatment before I/R with the CB-2 agonist JWH-133 to reach HSC depletion or the CB-1 agonist arachidonylcyclopropylamide to activate HSCs. Sinusoidal perfusion and liver transaminases were used as markers of I/R injury. Results. Hepatic I/R induced CD4+ T-cell recruitment in sinusoids. More than 25% of adherent CD4+ T-cells were colocalized with HSCs during reperfusion after ischemia, but not in the sham-operated mice. This is suggesting a direct cell-cell interaction. The HSC deactivation with JWH- 133 significantly attenuated the CD4+ T-cell recruitment in the post-ischemic liver and reduced I/R injury as compared to the vehicle-treated group. The HSC hyperactivation by CB-1, however, did not affect T-cell migration and even increased perfusion failure. Conclusion. Our in vivo data suggest i) that CD4+ cells interact with HSC upon their migration thought the endothelial layer; ii) a selective depletion/deactivation of HSC reduces T-cell-dependent I/R injury, whereas a HSC hyperactivation even accelerates the injury. Taken together, HSC might represent a potential target for future therapeutic strategies against T-cell-mediated I/R injury.