title: Modulating CD4+ T cell migration in the postischemic liver: hepatic stellate cells as new therapeutic target?
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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Jörg
authors.initials: J
authors.lastname: Reifart
authors.forename: Markus
authors.initials: M
authors.lastname: Rentsch
authors.forename: Konstantin
authors.initials: K
authors.lastname: Mende
authors.forename: Raffaele
authors.initials: R
authors.lastname: Coletti
authors.forename: Monika
authors.initials: M
authors.lastname: Sobocan
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.forename: Andrej
authors.initials: A
authors.lastname: Khandoga
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology; D002450:Cell Communication / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D019610:Cytoprotection; D004195:Disease Models, Animal; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism; D019707:Receptors, Chemokine / Q000235:genetics; D015427:Reperfusion Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control
chemical_list: C558396:Acta2 protein, mouse; D000199:Actins; D015415:Biomarkers; D063386:Cannabinoid Receptor Agonists; C571431:Cnr2 protein, mouse; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D019707:Receptors, Chemokine; D049452:Green Fluorescent Proteins