Natural killer T cells promote cholestatic liver disease in bile duct ligated mice — ASN Events
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Natural killer T cells promote cholestatic liver disease in bile duct ligated mice (#186)

Laura Valestrand 1 2 3 , Natalie L. Berntsen 1 2 3 , Fei Zheng 1 2 3 , Bjarte Fosby 4 , Tom H. Karlsen 1 2 3 5 , Pål Dag Line 3 4 , Xiaojun Jiang 1 2 , Espen Melum 1 2 5
  1. Norwegian PSC Research Center, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  2. Research Institute of Internal Medicine, Division of Surgery, Inflammatory Medicine and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  3. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  4. Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
  5. Section of Gastroenterology, Division of Surgery, Inflammatory Medicine and Transplantation, Surgery, and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway

Background:

Natural Killer T (NKT) cells are abundant in the mouse liver and we have previously demonstratedthat CD1d on cholangiocytes can present lipid antigens to NKT cells. We hypothesised that during cholestasis, i.e., when bile builds up in the liver, NKT cells play a regulatory role.

Methods:

To induce cholestasis we ligated the common bile duct of wild type (WT) and CD1d knockout (Cd1d-/-) mice. The mice were weighed daily and after three days we sampled livers for histological assessment and lymphocyte isolation for flow cytometry. Serum was sampled and analysed for alkaline phosphatase (AP), bilirubin and alanine transferase (ALT).

Results:

After bile duct ligation (BDL) (n=5) or sham operation (n=7) of WT mice there was a clear increase of the activation marker CD69 on the intrahepatic NKT cells at day 3 (1458 median fluorescense intensity (MFI) vs. 709 MFI, P<0.0001). There was no change in CD69 expression for the remaining hepatic T-cell population. We then investigated whether Cd1d -/- mice were protected against cholestasis. Mice lacking NKT cells had less weight loss following BDL than WT animals (weight loss day 3; 7% vs. 15%, P=0.0003). In line with this, the serum levels of the cholestatic parameters AP and bilirubin were significantly lower in Cd1d-/-mice; (AP; Cd1d -/-: 345 U/L vs. WT: 511 U/L, P=0.036) and (bilirubin; CD1d -/- :115 μmol/L vs. WT: 224 μmol/L, P=0.003).

Conclusion:

The intrahepatic NKT cell population is activated following BDL and Cd1d-/- mice are protected from cholestatic liver damage. This contrast previous reports in Jα18-/- mice. A possible explanation may be that the non-invariant NKT cells that the Cd1d -/- mouse also lacks, play the detrimental role during cholestasis.

  1. Schrumpf E, Tan C, Karlsen TH, et al. The biliary epithelium presents antigens to and activates natural killer T cells. Hepatology. April 2015. doi:10.1002/hep.27840.
  2. Wintermeyer P, Cheng C-W, Gehring S, et al. Invariant natural killer T cells suppress the neutrophil inflammatory response in a mouse model of cholestatic liver damage. Gastroenterology. 2009;136(3):1048-1059. doi:10.1053/j.gastro.2008.10.027.
  3. Duwaerts CC, Sun EP, Cheng C-W, van Rooijen N, Gregory SH. Cross-activating invariant NKT cells and kupffer cells suppress cholestatic liver injury in a mouse model of biliary obstruction. PLoS One. 2013;8(11):e79702. doi:10.1371/journal.pone.0079702.