Regulation of the adaptive immune response by chemokine scavenging receptors

Lead Research Organisation: University of Glasgow
Department Name: College of Medical, Veterinary &Life Sci

Abstract

When our bodies are invaded by foreign organisms such as bacteria or viruses, we mount what is called an immune response. This requires the careful orchestration of cell movement throughout the body, without which the immune response would not be properly developed. Much of the movement of the immune cells is regulated by specialised proteins which are called Chemokines. It is with these proteins that we work. We have identified molecules that can degrade some of the chemokines and therefore remove them from the area surrounding cells. We believe that this is important for the proper working of the immune system. The current proposal aims to study these molecules, which we call scavengers, in much more detail and to carefully examine their roles in helping the development of immune responses. The data we generate will therefore help us to understand the regulation of the immune response in much more detail and will have implications for our ability to therapeutically manipulate this process. In addition, sometimes chemokines can play deleterious roles and can be at the root cause of diseases such as arthritis and psoriasis. We believe that we might be able to use these scavenger molecules in disease contexts to switch off inflammation. We will therefore try to develop anti-inflammatory agents based on our knowledge of these scavenger molecules and will partner with a large Pharmaceutical company to help develop their therapeutic potential.

Technical Summary

Over the past 20 years much has been learnt about the fundamental roles played by chemokines and their receptors in regulating immune responses. We have been particularly interested in a subfamily of chemokine receptors which are characterised by promiscuous ligand binding and by an apparent inability to signal following ligand binding. Currently there are 4 members of this atypical chemokine receptor family and we have been instrumental in the identification and characterisation of 2 of these namely D6 and CCXCKR. Essentially, both are scavenger receptors, binding and internalising chemokine ligands and targeting them for intracellular degradation. D6 binds all the inflammatory CC chemokines and CCXCKR, in a complementary manner, binds the key homeostatic CC chemokines. These are therefore negative regulators of CC chemokine biology the identification of which has marked a major shift in our understanding of chemokine biology. Our studies on D6 indicate that it plays a strong role in regulating inflammatory responses in vivo. However, our more recent data suggest broader roles for D6 specifically in the context of regulation of adaptive immune responses. The ligand binding profile of CCXCKR immediately implicates it in adaptive immunity and thus we propose that these 2 atypical receptors represent a novel and important axis in the orchestration of the in vivo immune response. We now propose to unify our studies into D6 and CCXCKR under a single programme. We will use shared technologies to carefully investigate their roles in regulating chemokine availability, leukocyte migration and movement and the impact of this on adaptive immune responses. In addition, we have seen that an N terminal fragment of D6 retains the ability to bind chemokines. Given the promiscuity of D6 and its ability to bind all inflammatory CC chemokines, this N terminal peptide may represent a valuable therapeutic agent. We therefore also propose to initiate studies into the usefulness of chemokine scavenger receptor derived peptides as therapeutic agents. In the first instance, this will involve a biochemical analysis of the D6 N-terminal peptide as well as in vivo analyses of its ability to block inflammation in murine models. In addition, we will partner with colleagues at Novartis to develop the therapeutic potential of the D6 N-terminal peptide.

Publications

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Anselmo A (2014) Flow cytometry applications for the analysis of chemokine receptor expression and function. in Cytometry. Part A : the journal of the International Society for Analytical Cytology

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Asquith DL (2015) Targeting cell migration in rheumatoid arthritis. in Current opinion in rheumatology

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Bachelerie F (2014) New nomenclature for atypical chemokine receptors. in Nature immunology

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Bachelerie F (2015) An atypical addition to the chemokine receptor nomenclature: IUPHAR Review 15. in British journal of pharmacology

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Baldwin HM (2017) Elevated ACKR2 expression is a common feature of inflammatory arthropathies. in Rheumatology (Oxford, England)

 
Description Atypical chemokine receptors in West Nile Virus Infection 
Organisation National Institute of Allergy and Infectious Diseases (NIAID)
Country United States 
Sector Public 
PI Contribution Intitiation of collaboration to study the impact of D6 defficiency on responsiveness of mice to West Nile Virus infection.
Collaborator Contribution Initiating studies into West Nile Virus
Impact Nothing yet.
Start Year 2010
 
Description miRNA studies in rheumatoid arthritis 
Organisation University of Glasgow
Department Institute of Infection, Immunity and Inflammation
Country United Kingdom 
Sector Academic/University 
PI Contribution Development of technolgies for gene expression analysis in small numbers of cells.
Collaborator Contribution Initiating miRNA studies in the group.Initiated studies into D6 and Systemic Sclerosis.
Impact Kurowska-Stolarska, M., Alivernini, S., Ballantine, L.E., Asquith, D.L., Millar, N.L., Gilchrist, D.S., Reilly, J., Ierna, M., Fraser, A.R., Stolarski, B., et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 108, 11193-11198.
Start Year 2010
 
Description miRNA studies in rheumatoid arthritis 
Organisation University of Pavia
Department Rheumatology and Translational Immunology Research Laboratories [LaRIT]
Country Italy 
Sector Academic/University 
PI Contribution Development of technolgies for gene expression analysis in small numbers of cells.
Collaborator Contribution Initiating miRNA studies in the group.Initiated studies into D6 and Systemic Sclerosis.
Impact Kurowska-Stolarska, M., Alivernini, S., Ballantine, L.E., Asquith, D.L., Millar, N.L., Gilchrist, D.S., Reilly, J., Ierna, M., Fraser, A.R., Stolarski, B., et al. MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis. Proc Natl Acad Sci U S A 108, 11193-11198.
Start Year 2010
 
Description Alumni Networking 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Establishment of a Facebook networking site for alumni of Glasgow University's Immunology BSc course.

~300 alumni connected via social media and a site to advertise and disseminate job and postgraduate opportunities in Glasgow, UK, and internationally. Source of individuals to provide advice, and act as contacts, for current final year students.
Year(s) Of Engagement Activity 2011,2012,2013,2014,2015,2016
 
Description Big Biology Day 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Talk informed about the history and mechanisms of vaccination

Further requests for presentations at local schools
Year(s) Of Engagement Activity 2014
URL http://www.societyofbiology.org/get-involved/biologyweek/big-biology-days
 
Description Glasgow University Open Days 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Schools
Results and Impact Promotion of Glasgow University's research and teaching to ~100 prospective students and their parents.

Increase in interest in studying Immunology at Glasgow University.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
URL http://www.gla.ac.uk/about/visit/opendays/
 
Description Invited speaker Konstanz 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other academic audiences (collaborators, peers etc.)
Results and Impact Invited seminar at University of Konstanz, Germany

Increased European research profile
Year(s) Of Engagement Activity 2011
 
Description Member of the Glasgow Science Centre Scientific Advisory Panel 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Providing advice on direction etc for Glasgow Science Centre

Regular invitee to present talks at the Science Centre.
Year(s) Of Engagement Activity 2007,2008,2009,2010,2011
 
Description Primary School Science Fair (2012) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact 100 primary school children and their parents attended a science fair entitled 'Science Rocks' at which I ran an interactive workshop on the history and mechanisms of vaccination.

Feedback was excellent and further 'Science Rocks' events are planned in the local area.
Year(s) Of Engagement Activity 2012
 
Description School talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact 120 pupils attended a talk on my research

School pupils visit the lab for placements and to carry out their 6th year projects.
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011
 
Description Undergraduate teaching 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact Co-ordination of final year undergraduate Immunology course at Glasgow University, plus presentations on immunology and cancer/inflammation to ~80 third and fourth year undergraduate students every year. Dissemination of own research findings presented in the broader context of the field.

Education of local young people. Each year 10-12 Immunology graduates undertake PhD studies, with others entering Masters studies or other courses (Medicine, Dentistry, Vet Medicine).
Year(s) Of Engagement Activity Pre-2006,2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016