Introduction Primary Sclerosing Cholangitis (PSC) is an incurable chronic immune mediated biliary disease that occurs in individuals with IBD. We have previously reported aberrant expression of the gut chemokine, CCL25 in the human PSC liver and the recruitment of CCR9 expressing gut derived T cells. In order to gain further insights into the consequences of aberrant CCL25 expression in the liver in PSC, we induced CCL25 in the murine liver and assessed biliary inflammation in-vivo.
Methods To clarify the functional role of CCL25 expression in the liver, we generated a murine liver specific knock-in of CCL25 expression and tested the effects on immune mediated cholangitis using the Ova-Bil model of antigen driven biliary injury. Immune cell phenotyping and isolation were performed using flow cytometry. Liver injury was assessed by ALT measurements and histopathology. pDC function was assessed ex-vivo in co-culture with naive transgenic TCR T cells
Results Ova-Bil x CCL25KI mice developed significantly less liver injury than wt Ova-Bil controls. Flow cytometry revealed increased numbers of CCR9+ pDCA-1+ plasmacytoid dendritic cells (pDC) in the Ova-Bil x CCL25KI livers. CCR9-/- x Ova-Bil mice developed significantly worse liver injury compared to wt Ova-Bil controls and severely lacked pDCs in the liver. Adoptive transfer of wt pDCs to CCR9-/- x Ova-Bil mice rescued the phenotype and reduced the degree of liver injury comparable to wt Ova-Bil controls. In vitro studies demonstrated the ability of liver-derived pDCs to induce regulatory T cells in a retinoic acid dependent manner as a possible mechanism by which CCR9+ pDCs are able to control liver injury.
Conclusion Aberrant expression of CCL25 in the liver enhances recruitment of CCR9+ pDCs and appears to be an attempt to limit the extent of hepatic inflammation in PSC. Regulatory effects of CCR9+ pDCs appears to be at least in part mediated through the expansion of hepatic regulatory T cells.
Disclosure of Interest None Declared
Eksteen B, Grant AJ, Miles A, et al. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J.Exp.Med. 2004; 200:1511–1517.