Jörg Reifart1, Markus Rentsch, Konstantin Mende, Raffaele Coletti, Monika Sobocan, Wolfgang E Thasler, Andrej Khandoga. 1. 1 Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany. 2 Walter-Brendel Centre for Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany. 3 Department of Cardiology, Klinikum der Universität München, Ludwig-Maximilians-Universität München, Munich, Germany.
Abstract
BACKGROUND: CD4+ T cells play a critical role during hepatic ischemia-reperfusion (I/R) injury although the mechanisms of their migration in the postischemic liver remain unclear. 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. 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, suggesting a direct cell-cell interaction. The HSC deactivation with JWH-133 significantly attenuated the CD4+ T cell recruitment in the postischemic 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 that CD4+ T cells interact with HSCs on their migration into the hepatic parenchyma, and a depletion or deactivation of HSCs protects the liver from T cell-dependent I/R injury.
BACKGROUND: CD4+ T cells play a critical role during hepatic ischemia-reperfusion (I/R) injury although the mechanisms of their migration in the postischemic liver remain unclear. 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. CD4+ T cell-HSC interactions were visualized after infusion of fluorescence-labeled CD4+ T cells into Cx3CR1mice (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, suggesting a direct cell-cell interaction. The HSC deactivation with JWH-133 significantly attenuated the CD4+ T cell recruitment in the postischemic 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 that CD4+ T cells interact with HSCs on their migration into the hepatic parenchyma, and a depletion or deactivation of HSCs protects the liver from T cell-dependent I/R injury.
Authors: Sebastian Pratschke; Hannah Arnold; Alfred Zollner; Michael Heise; Andreas Pascher; Peter Schemmer; Marcus N Scherer; Andreas Bauer; Karl-Walter Jauch; Jens Werner; Markus Guba; Martin K Angele Journal: Transplant Direct Date: 2016-05-04