Role of CXCR6/CXCL16 in steatohepatitis

Lead Research Organisation: University of Birmingham
Department Name: Immunity and Infection

Abstract

Liver disease is a significant health problem in the UK where rates of liver disease are rising as a consequence of hepatitis C infection, rising rates of alcoholic liver disease (ALD) and a high prevalence of non-alcoholic fatty liver disease (NALFD) a liver disease related to obesity, diabetes and high blood pressure. Despite their different causes most chronic liver diseases arise as a consequence of an inflammatory response to liver injury that causes scarring and destruction of the liver leading to liver failure. The inflammation in the liver is due to white blood cells leaving the bloodstream and entering liver tissue where they can orchestrate liver damage. This process is controlled by numerous molecules in the liver and on white cells that promote their entry and retention in the liver.
We propose to focus our research on one of these molecules, a chemokine called CXCL16 and its corresponding receptor on white cells, CXCR6. We have already shown that CXCR6 is concentrated on white cells that cause liver damage and I will now determine precisely what this receptor does and by using recently developed specific inhibitors of CXCR6, elucidate the inflammatory process and investigate new means of treating it.

Technical Summary

Aim: The chemokine receptor CXCR6 is expressed by specific subsets of effector lymphocytes that we have shown to be present within the inflamed liver. The present project will define the role of CXCR6 and its chemokine ligand CXCL16 in the pathogenesis of hepatitis and liver injury with the object of defining CXCR6 as a therapeutic target in liver disease.
Objectives: To define
i. CXCL16 expression on parenchymal and non-parenchymal cells in normal and diseased liver
ii. The functional lymphocyte subsets that express CXCR6 in the inflamed liver
iii. The role of CXCR6/CXCL16 in lymphocyte recruitment to and positioning within the liver
iv. The effect of manipulating CXCL16/CXCR6 in murine models of liver inflammation
Design and Methodology:
1) Human studies: lymphocytes, parenchymal and non-parenchymal cells will be isolated from livers removed at transplantation in our Unit allowing me to define a) expression patterns of CXCL16 and CXCR6 in normal and diseased liver using immunohistochemistry, flow cytometry and qRT-PCR b) functional lymphocyte subsets that express CXCR6 using flow cytometry and intracellular cytokine staining c) the function of CXCR6/CXCL16 in the recruitment of lymphocytes using flow-based adhesion assays incorporating human hepatic endothelium and stellate cells to model the hepatic sinusoid in vitro d) the effect of CXCR6/CXCL16 interactions on the activation, survival and cytokine secretion of interacting lymphocytes and epithelial cells.
2) Murine models of liver inflammation: models established in our laboratory will be used to determine the effect of inhibiting CXCR6 in vivo using blocking antibodies, small molecule inhibitors and genetically modified mice to define the role of CXCR6 in liver inflammation in vivo.
3) Development of therapeutic CXCR6 inhibitors: I will spend time at Chemocentryx Inc in Paolo Alto testing the potential of novel small molecule inhibitors to block CXCR6 dependent responses and then apply the inhibitors to the in vitro and in vivo models available in Birmingham.
Scientific opportunities/Medical opportunities
The project will provide a superb training in cellular immunology within the Centre for Liver Research and the MRC Centre for Immune Regulation. I will participate in the development of novel CXCR6 antagonists during my stay at Chemocentryx, a SME who lead the world in the development of chemokine receptor antagonists. The information I generate will potentially lead to proof of concept clinical trials in liver disease using CXCR6 inhibitors within 5 years.

Publications

10 25 50
 
Description Sheila Sherlock Physician Scientist Fellowship
Amount € 20,000 (EUR)
Organisation European Association for the Study of the Liver (EASL) 
Sector Charity/Non Profit
Country Switzerland
Start 04/2015 
End 10/2015
 
Description Sheila Sherlock Travelling Fellowship in Hepatology
Amount £3,500 (GBP)
Organisation Royal College of Physicians of London 
Sector Learned Society
Country United Kingdom
Start 06/2014 
End 08/2014
 
Description Acute liver failure research 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of role of CCR9 expressed by monocytes/macrophages in acute liver failure
Collaborator Contribution Investigations in ex vivo human samples
Impact Abstract submitted to EASL 2015
Start Year 2014
 
Description Acute liver failure research 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution Investigation of role of CCR9 expressed by monocytes/macrophages in acute liver failure
Collaborator Contribution Investigations in ex vivo human samples
Impact Abstract submitted to EASL 2015
Start Year 2014
 
Description ChemoCentryx collaboration 
Organisation ChemoCentryx
Country United States 
Sector Private 
PI Contribution Ongoing collaboration with ChemoCentryx after first visit in 2013, to pursue research into role of CCR2 in fatty liver disease with view to potential therapy
Collaborator Contribution Financial cost of trips to US. Providing reagents, mice and new drugs
Impact Abstracts at EASL 2014 and submitted for EASL 2015
Start Year 2013
 
Description Centre for Liver Research public engagement 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Taking part in research fair held at Queen Elizabeth Hospital Birmingham for patients and public

The Centre for Liver Research was awarded best stand
Year(s) Of Engagement Activity 2014
 
Description Public and Patient Involvement Committee 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Attended local PPI group to present proposed research projects for discussion

Discussion regarding design of trials with PPI group
Year(s) Of Engagement Activity 2014