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 in remain unclear. Recently, T cells were suggested to colocalize with hepatic stellate cells (HSCs) in the liver during viral hepatitis. Here, we answered the question i) whether HSCs interact with T cells during I/R of the liver, and ii) whether modulation of HSC activity is protective against T cell-dependent I/R injury.
Methods: Migration of freshly isolated and fluorescence-labeled CD4+ T cells was analyzed using intravital videofluorence microscopy in sham-operated mice and in three different groups mice after I/R (90min/120min, n=7 each group). Sinusoidal perfusion and liver enzyme activities were determined as markers of I/R injury.
Results: T cell-HSC interactions were visualized in vivo after infusion of fluorenscence-labeled CD4+ T cells into Cx3CR1 mice (mice exhibiting GFP-labeled HSCs) after I/R. Since the activation of HSC is controlled by endocannabioid receptors CB-1 and CB-2, we infused either the CB-2 agonist JWH-133 (0.2 mg/kg) to reach HSC depletion or the CB-1 agonist ACPA (1 mg/kg) to activate HSC to mice after I/R. Hepatic I/R induced CD4+ T cell recruitment in sinusoids (8.1±0.5/acinus, p<0.05 vs. 2.8±0.2/acinus in sham). In contrast, the HSC deactivation with JWH-133 significantly attenuated the CD4+ T cell recruitment in the postischemic liver (3.7±0.6/acinus) and reduced I/R injury (AST: 1996±261, AST: 2159±323U/L, p<0.05) as compared to the vehicle-treated group (5648±540 and 6480±521U/L, respectively). HSC hyperactivation via 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 into the hepatic parenchyma; ii) a selective depletion/deactivation of HSC reduces T cell-dependent I/R injury. Thus, HSC might represent a potential target for future therapeutic strategies against T cell-mediated I/R injury.
To cite this abstract in AMA style:Khandoga A, Mende K, Rentsch M, Reifart J. Modulating T Cell Migration in the Postischemic Liver: Hepatic Stellate Cells as New Therapeutic Target? [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/modulating-t-cell-migration-in-the-postischemic-liver-hepatic-stellate-cells-as-new-therapeutic-target/. Accessed April 7, 2020.
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