A novel role for the chemokine lymphotactin and its receptor in trigeminal sensitisation

Lead Research Organisation: University of Sheffield
Department Name: Clinical Dentistry

Abstract

Chemokines are a large family of small secreted proteins that regulate the migration of white blood cells with a well-established role in coordinating immune responses in peripheral tissues. However, within the last decade a range of studies has demonstrated that chemokines also have wide-reaching effects in the nervous system, where they have been shown to have diverse effects in a range of processes, regulating development, inflammation and communication between cells. Consequently, they have been implicated in a variety of disease states including multiple sclerosis, Parkinson's, Huntingdon's and Alzheimer's diseases, and chronic pain. This proposal focuses on a relatively little-studied member of the large chemokine family. Our recent work provides the first demonstration that this particular chemokine and its receptor are expressed in the nervous system. Evidence from other studies now clearly shows that chemokines can initiate and maintain increased activity within peripheral and central pain pathways and thus contribute to the development of chronic pain. This raises the possibility that the chemokine we propose to study may also be important in the development of chronic pain and other diseases. We will investigate the role of the chemokine in pain from the mouth and face; as this area is supplied by the trigeminal nerve, pain from this region is known as trigeminal pain. The overall aims of the study are to determine which components of the trigeminal pain pathway express the chemokine and its receptor, and to investigate its role in increased activity in this pathway. This will enable us to establish its potential contribution to the development of chronic pain in the oro-facial region. Initially we will determine the expression of the chemokine and its receptor in specific cell types within normal rat trigeminal tissues that are involved in pain initiation and processing, including the tooth pulp, a branch of the trigeminal nerve, and elements of central pain pathways. We will then establish how their expression is altered in two conditions, nerve injury and inflammation, known to produce increased activity in pain pathways. This activity plays a key role in the initiation of chronic pain. We will determine whether levels of expression correlate with the time course of development of increased activity, as determined in our previous studies. We have access to unique archives of human tissues stemming from our provision of a national service for advice and management of patients who sustain trigeminal nerve injuries, and from treatment of patients with dental pain. We will use this tissue to examine the expression of the chemokine and receptor in human tooth pulps and injured nerves from patients with known clinical pain histories, enabling us to establish whether expression at sites of nerve injury or inflammation in human tissue correlates with the presence of pain. We will also carry out a series of functional studies to determine the effects of this chemokine within a region of the brainstem involved in the central processing of trigeminal pain. These studies will establish whether the chemokine is able to influence activity in different cell types in this region and investigate how it may modulate signalling between and within cells. Thus we will be able to establish whether this molecule is capable of enhancing activity in the central nervous system, and identify any potential role in modifying activity in central pain pathways. This project will enable us to determine any putative role for this chemokine within peripheral and central pain pathways and establish whether either the chemokine or its receptor may provide a target for novel analgesics. This, in turn, may lead to the development of novel therapies for chronic pain and potentially other neurological conditions for which there is currently no reliable treatment, thus substantially improving quality of life for patients.

Technical Summary

Several chemokines have recently been identified within the nervous system, where they have been shown to have diverse effects, regulating neuronal development, neuroinflammation and synaptic transmission, and have been implicated in the initiation and maintenance of exaggerated pain states. Recent work in Prof Boissonade's laboratory provides the first demonstration that the relatively little-studied chemokine, lymphotactin (XCL1), and its receptor (XCR1) are expressed in the nervous system. The overall aim of this study is therefore to characterise for the first time the expression of XCL1 and XCR1 in the trigeminal system, and to investigate their putative role in hyperexcitability, signalling and trigeminal pain. We will characterise XCR1 and XCL1 expression in normal rat trigeminal tissues (tooth pulp, lingual nerve, trigeminal ganglion and trigeminal nucleus) and identify specific structures demonstrating expression, eg neuronal structures, immune cells and glial cells. We will also determine in our established animal models, whether XCR1 and XCL1 expression are altered by nerve injury or inflammation and establish any correlation with the development of hyperexcitability. We will examine the expression of the XCL1 and XCR1 in human tooth pulps and injured nerves using our unique archives of human tissues from patients with known clinical pain histories. This will enable us to establish whether expression at sites of nerve injury or inflammation correlates with the presence of pain. The above will be achieved using a range of immunocytochemical and image analysis techniques. Using an in-vitro trigeminal slice preparation we will determine whether XCL1 activates intracellular signalling molecules, eg p38 and ERK, in the trigeminal nucleus within specific cell types, eg astrocytes, microglia or neurones, and probe the cellular mechanisms of XCL1-induced activation.

Planned Impact

All research scientists working in the very broad field of chemokine research will benefit from this research. In addition to their well-established role in co-ordinating peripheral inflammatory responses, it is now increasingly clear that chemokines play a fundamental role in signalling within the nervous system, and they have been shown to be involved in diverse events including neuronal development, neuroinflammation and synaptic transmission. Thus there will be a wide range of scientists who will benefit from this research; these are discussed in detail in the Academic Beneficiaries section. The wider beneficiaries are discussed below. Patients with pain and other neurological disease: Because of their wide-reaching roles in the nervous system, chemokines have been implicated the pathogenesis of numerous neurological conditions including multiple sclerosis, Parkinson's, Huntingdon's and Alzheimer's diseases, and chronic pain. Our study will provide the first description of the distribution and neuromodulatory effects of a relatively little-studied chemokine within the nervous system, focusing on areas related to trigeminal pain. However, neuromodulatory effects of this chemokine are likely to be wide-reaching, thus there is potential that this molecule and its receptor may represent a therapeutic target for a range of conditions. If this leads to the development of novel therapies with improved side effect profiles, it could provide a substantially improved quality of life for patients. Many of the conditions described above are more prevalent in the older population and thus any novel drugs may contribute to improved health during ageing. In order to ensure that our data is as widely disseminated as possible, we will inform research scientists in all relevant fields through publication in a broad spectrum of high impact journals with copies made available through PubMed Central, and present data at wide-ranging international conferences. We will identify other collaborators with interest in other neurological areas to carry out further studies, and inform clinicians and patient user groups as appropriate (see Pathways to Impact). Pharmaceutical Industry: The data from the proposed study will potentially provide information regarding targets for the development of therapies for a wide range of neurological disorders (see above). The increased prevalence of these disorders due to the ageing population, coupled with a lack of drugs to cater for these disorders, has resulted in considerable interest in the development of novel therapeutics to address these areas of unmet clinical need. The interest of our industrial partner, Pfizer, lies primarily in the identification of targets for novel analgesics. However, as described above, there is considerable scope for any novel targets identified in this project to be utilised for the development of therapies for other neurological disorders. The research staff: The research staff employed on this grant will gain interdisciplinary expertise as a result of this collaborative project. In addition, working with our industrial collaborators will enable them to gain a broader perspective, particularly with respect to the field of drug discovery. Our interest in wide dissemination of our findings will bring opportunities to publish in new areas, and enable work to be presented to a diverse audience, which will strengthen and develop the direction of their careers.

Publications

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Boissonade FM (2018) Sheffield Pain Network

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Boissonade FM (2018) Pain: from molecule to man

 
Description This is the first study to identify XCR1 in the nervous system and to describe a role for XCL1/XCR1 in modulating neuronal excitability. Three days following a peripheral nerve injury, XCR1 was expressed at high levels at the injury site in nerve fibres, CD45+ve leucocytes and Schwann cells. The functional data reveal that in the presence of XCL1, there are increased spontaneous low-threshold voltage oscillations, which may represent a form of on-going activity within the Vc nociceptive circuitry. This activity could contribute to the manifestation of spontaneous pain or drive sensitization-related phenomena such as allodynia or hyperalgesia. Data from this study provide the first evidence that XCL1 and XCR1 may play a role within peripheral and central pain pathways, providing potential as a target for novel analgesics.
Exploitation Route We are currently further investigating the role of this chemokine and its receptor in other CNS disease states. This work is funded by a BBSRC DTP studentship and is a collaborative project with the Sheffield Institute for Translational Neuroscience.

We have been awarded funding by Eli Lilly and the BBSRC (impact acceleration award) to further investigate this axis as an analgesic target.

We have also been awarded funding by Versus Arthritis to investigate the role of this chemokine in Arthritis pain.
Sectors Healthcare

 
Description We are investigating the potential for drug discovery and have been awarded funding by Eli Lilly and the BBSRC (impact acceleration award) to carry out this work
First Year Of Impact 2018
Sector Healthcare
Impact Types Societal

 
Description BBSRC Sparking Impact Award
Amount £8,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
 
Description BBSRC Sparking Impact Award
Amount £7,500 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start  
 
Description BBSRC White Rose DTP
Amount £91,452 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 10/2014 
End 09/2018
 
Description EU Marie Curie Incoming International Fellowship
Amount € 310,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start  
 
Description Eli Lilly project grant
Amount £60,000 (GBP)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 01/2019 
End 06/2020
 
Description Identification of genetic and protein modifications linked with neuropathic and inflammatory pain
Amount £100,279 (GBP)
Funding ID BB/T508159/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 09/2023
 
Description Identification of genetic and protein modifications linked with neuropathic and inflammatory pain
Amount £22,000 (GBP)
Organisation Eli Lilly & Company Ltd 
Sector Private
Country United Kingdom
Start 10/2019 
End 09/2022
 
Description Impact acceleration award
Amount £40,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 06/2020
 
Description Industrial & Translational Postgraduate Student Collaboration Programme "HEFCE Catalyst Studentships"
Amount £10,000 (GBP)
Organisation Higher Education Funding Council for England 
Sector Public
Country United Kingdom
Start 10/2016 
End 03/2017
 
Description Lymphotactin in Arthritis pain. Versus Arthritis grant
Amount £370,000 (GBP)
Funding ID 22452 
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2020 
End 05/2023
 
Description MRC - Confidence in Concept
Amount £62,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 09/2016 
End 12/2017
 
Description MRC Centenary Award
Amount £15,800 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description MRC Confidence in Concept Award
Amount £50,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start  
 
Description MRC Industrial CASE studentship
Amount £50,000 (GBP)
Funding ID G0800133/3-1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2011 
End 09/2014
 
Description University of Sheffield - Festival of the Mind
Amount £5,000 (GBP)
Organisation University of Sheffield 
Sector Academic/University
Country United Kingdom
Start 04/2018 
End 10/2018
 
Description University of Sheffield Faculty/Pfizer PhD Studentship
Amount £60,000 (GBP)
Organisation University of Sheffield 
Department School of Clinical Dentistry Sheffield
Sector Academic/University
Country United Kingdom
Start  
 
Description University of Sheffield Festival of the Mind
Amount £5,000 (GBP)
Organisation University of Sheffield 
Sector Academic/University
Country United Kingdom
Start  
 
Description Collaboration established with Eli Lilly to further investigate the role of the chemokine lymphotactin in neuropathic pain. 
Organisation Eli Lilly & Company Ltd
Country United Kingdom 
Sector Private 
PI Contribution Our research team provided the underpinning research suggesting that the chemokine may play a role in neuropathic pain. All of the work is being carried out in my laboratory. The work is being funded by a grants from Eli Lilly and a BBSRC impact acceleration award.
Collaborator Contribution Funding for the project.
Impact Publications are in preparation
Start Year 2019
 
Description Festival of Medicine, Dentistry and Health 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Interactive activity exploring nerve function stimulated Y6 children's' interest

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Year(s) Of Engagement Activity 2014
 
Description Festival of the Mind 2012 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk sparked questions and discussion afterwards

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Year(s) Of Engagement Activity 2012
 
Description Festival of the Mind 2014 - You've Got a Nerve! (Art and Animation Installation) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Art installation ignited interest in nerve injury and repair

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Year(s) Of Engagement Activity 2014
 
Description Interactive exhibit as part of 'Discovery Night' an element of National Science Week 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Exhibit and activities to explain research programmes in the University of Sheffield.
Year(s) Of Engagement Activity 2018
URL https://www.sheffield.ac.uk/discoverynight
 
Description National Science and Engineering Week - Researchers' Night 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? Yes
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Raised public interest and awareness

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Year(s) Of Engagement Activity 2013,2014
 
Description Public engagement actvity 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact This exhibit, illustrated the wide range of oral and dental disease that we treat in our patients, and explained how research across the Dental School is helping to improve treatment for these problems.
The exhibit consisted of a giant mouth with specific regions illustrating a range of oral disease conditions (eg, congenital tooth disorders, tooth decay, oral cancer and other oral mucosal disease, salivary gland disease, gum disease, nerve injury etc), to highlight the problems that we treat in our patients. The diseased regions were linked to smaller adjacent exhibits (eg videos, posters, demonstrations, craft activities etc), which provided details of our research and described how this research is advancing treatment and improving patients' quality of life.
Year(s) Of Engagement Activity 2018
URL https://festivalofthemind.group.shef.ac.uk/2018-programme/
 
Description Researcher's Night. For one night, hundreds of universities across Europe open their doors to the public. Sheffield is one of handful of UK universities taking part. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The University of Sheffield opened its doors to allow visitors to explore the latest research at the University, through talks, exciting demonstrations and hands on activities. Aimed at secondary school students, sixth formers and adults, Researchers' Night enabled visitors to interact with a vast array of research projects from across the University.

The activities related to this research award were:

Eyes, Ears, Mouth, Nose and Fingers A neuroscientist's understanding of the senses.
Ou
Year(s) Of Engagement Activity 2016
URL http://www.sheffield.ac.uk/researchersnight/programme
 
Description The Mobile University 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation sparked questions and discussion

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Year(s) Of Engagement Activity 2013
 
Description University of Sheffield's Festival of the Mind - A showcase for the University's world-leading research. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The festival, which pairs University academics with experts from Sheffield's cultural and creative industries, attracted 50,000 visitors to its performances, talks, exhibitions, virtual reality experiences and interactive events designed to educate, inform and create debate.

Professor Vanessa Toulmin, Director of City and Cultural Engagement at the University of Sheffield, said: "Festival of the Mind 2016 has captured the spirit of invention and collaboration which makes Sheffield such a great place to live.

"We have had overwhelmingly positive feedback to this year's festival with some wonderful comments from visitors who have been inspired by our world-leading research.

"Ninety-two per cent of visitors rated the festival as excellent and sixty-eight per cent said it had changed their perception of our research in a positive way."

During the festival, footfall in the city centre increased by 23 per cent compared to the same period the previous year. The Moor Market and Winter Garden areas saw an increase of 51 per cent.

Vanessa continued: "Festival of the Mind is an example of what incredible things can be achieved when you bring together some of the world's leading researchers and the best creative minds in the industry.

The exhibit related to this research award consisted of a short film called "13 Teeth", a gothic thriller about a man who thinks the voices in his head are coming from his teeth. His quest to extract them (eek!) leads to a shocking revelation. Based on Gwynne Jones's narrative poem, the film mixes live action and animation to brilliantly unsettling effect. It asks the big question: what is behind consciousness?
In the accompanying documentary, The Making of 13 Teeth, the academics involved in the project (Boissonade, Bird, Birkhead) talk us through some of the film's most striking images, including skeletons, nerves and teeth; and their research related to these.
Year(s) Of Engagement Activity 2016
URL https://www.sheffield.ac.uk/news/nr/university-of-sheffield-festival-of-the-mind-inspires-the-city-1...