Trafficking of monocytes and their differentiation to dendritic cells and macrophages in the human liver

Lead Research Organisation: University of Birmingham
Department Name: Clinical and Experimental Medicine

Abstract

Most liver diseases occur as a consequence of uncontrolled inflammation mediated by white blood cells recruited into the liver from the blood. White blood cells enter the liver via channels or sinusoids that are lined by specialised cells called endothelial cells which the white cells must bind to and migrate between before they can enter liver tissue. We propose that this process will a) determine the nature of the cells recruited and b) determine how those cells become activated and thereby the outcome of liver injury. We have developed complex test tube models in which combinations of human liver cells are grown under particular conditions that mimic the environment within the diseased liver sinusoids. We will use these models to investigate how white cells are recruited and how interactions with sinusoidal cells can define the activation status of the cells during their recruitment. Understanding this process will elucidate why in some circumstances white blood cells can promote the repair of the damaged liver whereas in other circumstances they amplify liver injury. We hope to use this information to develop new therapies to manipulate white blood cells in the liver in favour of repair rather than continuing liver damage and thereby to reverse inflammatory liver disease and prevent liver cirrhosis.

Technical Summary

Circulating monocytes gives rise to tissue-resident macrophages and dendritic cells which are critical regulators of inflammatory and immune-mediated responses. The liver contains functionally distinct macrophages and dendritic cells (DC) that contribute to local immune responses by activating immune responses or promoting inflammatory resolution. Thus activated DCs induce immune responses to pathogens whereas resting DCs induce tolerance; and although some activation pathways result in macrophages that drive immune-mediated liver injury others result in reparative macrophages that promote resolution. The balance of intrahepatic monocyte/macrophages activation will thus be a critical determinant in the outcome of liver injury. At least two phenotypically distinct subsets of monocytes circulate in blood which can be distinguished by their expression of specific cell surface markers. These cells enter the liver by migrating across sinusoidal endothelium and through the subendothelial matrix where they interact with other cells including fibroblasts and hepatocytes. We propose that the activation and differentiation of monocytes into liver DCs and macrophages will be shaped by interactions with sinusoidal endothelial cells during transmigration and then with matrix and parenchymal cells once the monocytes are in tissue. We have developed co-culture models using primary human liver cells that recapitulate the sinusoidal cellular environment in vitro. We will use these models to determine 1) the molecules involved in recruiting different subsets of monocytes from the blood into liver 2) the ability of underlying hepatocytes or fibroblasts to modulate this process in the presence of inflammatory stimuli 3) the effect of interactions with endothelium, subendothelial matrix and other liver cells on subsequent monocyte differentiation and activation. We hypothesise that migration through the multi-cellular hepatic sinusoids will confer on monocytes a distinct phenotype and function that will determine how these cells behave within liver tissue. Modulation of these processes may suggest ways in which monocyte recruitment and activation can be manipulated to favour resolution rather that persistence of inflammation in chronic liver disease.

Publications

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Adams DH (2010) Mechanisms of immune-mediated liver injury. in Toxicological sciences : an official journal of the Society of Toxicology

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Adams DH (2018) Could endothelial TGFß signaling be a promising new target for liver disease? in Expert review of gastroenterology & hepatology

 
Description EME Project:12/165/31 - Targeting vascular adhesion protein-1 (VAP-1) for the treatment of liver fibrosis: a study of efficacy and mechanisms in patients with primary sclerosing cholangitis (PSC).
Amount £1,000,000 (GBP)
Funding ID EME Project:12/165/31 - Targeting vascular adhesion protein-1 (VAP-1) for the treatment of liver fibrosis: a study of efficacy and mechanisms in patients with primary sclerosing cholangitis (PSC). 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 01/2019
 
Description MRC/NIHR EME
Amount £550,000 (GBP)
Funding ID EME Project:09/160/24 - A Phase II randomised clinical trial of conditioning cyclophosphamide and chemoembolisation with or without vaccination with dendritic cells pulsed with HepG2 lysate ex vivo in patients with Hepatocellular Carcinoma: IMMUNOTACE 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2015 
End 02/2019
 
Description Edinburgh 
Organisation University of Edinburgh
Department MRC Centre for Inflammation Research
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed a successful local collaboration with my colleague Dr Newsome andPorfs Forbes and Iredale in Edinburgh resulting an ongoing collaboration which ahs contributed to a recent MRC grant awarded in 2009.
Collaborator Contribution We have several ongoing collaborations sharing technology and expertise
Impact Ongoing publications and research collaborations
Start Year 2008
 
Description Research fellowship 
Organisation Albert Ludwig University of Freiburg
Country Germany 
Sector Academic/University 
PI Contribution EU funded research fellowship for Nico Buettner to visit our laboratory for 2 years
Collaborator Contribution Funded research fellow
Impact Conference presentation Publications in preparation
Start Year 2014
 
Description University of Aachen 
Organisation RWTH Aachen University
Country Germany 
Sector Academic/University 
PI Contribution Collaboration investigating leukocyte recruitment to the liver and in porviding research training for DFG funded clinical acdemics
Collaborator Contribution Scientific collaboration
Impact Publications Grants Training
Start Year 2012
 
Description Guardian 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact -Article in the Guardian on liver disease and transplantation www.guardian.co.uk/society/2008/nov/28/organ-donation-health-policy-transplant

Incraesed public profile
Year(s) Of Engagement Activity 2008
 
Description PPI initiatve 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact 20 members of the public and patients attended a seminar/workshop on liver research in Birmingham

Panel agreed to review our research patient information sheets
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description PSC 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Hosted meeting of the PSC patient group to discuss our research
Took on role as Trustee of the Charity in 2013

Asked to host the meeting on an annual basis
Helped develop a research funding programme for the charity
Helped write guieldlines and provide clinical advice
Year(s) Of Engagement Activity 2009,2010,2011,2012,2013,2014
URL http://www.pscsupport.org.uk/?gclid=Cj0KEQiAp4yjBRCE_enjmpug944BEiQATCpLvU1wXwOybMo7BSFeWs_AEICLJAiy...
 
Description Public engagement 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Participants in your research and patient groups
Results and Impact PSC Trust meeting London

Discussion of the potential for stem cell therapy in liver disease. A funding initiative to support genomics in liver disease.
Year(s) Of Engagement Activity 2007
 
Description Schools 
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 Schools
Results and Impact -Students from local schools come to the department to learn about research and to carry out short projects

Goldcrest award and Nuffield Bursary award
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012,2013,2014,2015
 
Description Trustee PSC Support 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Trustee of patients support charity responsible for overseeing charity and organising meeting to share research advances
Year(s) Of Engagement Activity 2015,2016,2017
URL http://www.pscsupport.org.uk/?gclid=CjwKEAjwqZ7GBRC1srKSv9TV_iwSJADKTjaDl5WWgqCsixq9oG84SRlUY8FyF_2U...
 
Description World hepatitis day 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact -Hosted public meeting for World hepatitis day attended by patient groups, politicians, press. Featured on Kerrang Radio & Naked scientist website http://www.thenakedscientists.com/HTML/podcasts/specials/show/2009.06.10/

Increased profile
Year(s) Of Engagement Activity 2009