ERA-NET NEURON: Identification and study of different immune cell populations and their role in chronic pain
Lead Research Organisation:
King's College London
Department Name: Wolfson Centre for Age Related Diseases
Abstract
About one in five individuals is likely to suffer from chronic pain in their lifetime. Many diseases and
conditions can cause intractable pain, for instance rheumatoid arthritis or nerve damage caused by
injury or virus-infection, and these pains frequently have devastating consequences. While scientists
have yet to identify fool-proof treatment options, they have made some important advances in
understanding what goes wrong in the body of a chronic pain sufferer. In particular, we now know that
the way our immune system responds to injury or infection can have an important impact on chronic
pain. What is less clear, is which cell types are involved exactly and what it is about their responses
that is so damaging to the surrounding neurons. Could the nature of this immune response predispose people towards developing chronic pain?
In this grant, we would like to investigate these questions further. We will use new experimental
methods to isolate immune cells and study their molecular responses. We will also study patients
suffering from acute pain to identify whether their immune response makes them more or less likely to
develop persistent pain. Our experiments have the potential to identify risk factors for chronic pain as well as novel avenues for treatment.
conditions can cause intractable pain, for instance rheumatoid arthritis or nerve damage caused by
injury or virus-infection, and these pains frequently have devastating consequences. While scientists
have yet to identify fool-proof treatment options, they have made some important advances in
understanding what goes wrong in the body of a chronic pain sufferer. In particular, we now know that
the way our immune system responds to injury or infection can have an important impact on chronic
pain. What is less clear, is which cell types are involved exactly and what it is about their responses
that is so damaging to the surrounding neurons. Could the nature of this immune response predispose people towards developing chronic pain?
In this grant, we would like to investigate these questions further. We will use new experimental
methods to isolate immune cells and study their molecular responses. We will also study patients
suffering from acute pain to identify whether their immune response makes them more or less likely to
develop persistent pain. Our experiments have the potential to identify risk factors for chronic pain as well as novel avenues for treatment.
Technical Summary
Chronic pain is a major burden on the life of sufferers and society as a whole. While our understanding
of the condition is progressing, adequate therapies are still lacking and millions of people are living
with persistent, debilitating pain that has no discernable function.
One of the most promising developments in recent years has been the recognition that microglial
activation is a key driver of neuropathic pain. This unexpected role of neuroinflammation brings us
tantalizingly close to potential new drug treatments. However, in order to translate this potential, we
need answers to several key questions.
First and foremost, which cells are driving chronic pain? The contribution of infiltrating monocytes versus resident microglial cells is unknown. Resolving this issue is a critical first step to target the
neuroinflammatory process. A second key question is how exactly do resident microglia and infiltrating
monocytes respond in different pain states? How do they mediate pro-inflammatory (and possibly antiinflammatory)
cascades? And over what time courses? Are they able to maintain an epigenetic, molecular memory of previous insults, which might then 'prime' them to drive a chronic pain state?
The aim of our proposal is to seek answers to these questions. A vital and obligatory step, if we hope
to develop novel analgesic strategies directed at spinal neuroinflammatory processes.
We are bringing together three laboratories, each with highly-specialised expertise that will enable a unique synergy. In the McMahon laboratory, we will use novel cell sorting techniques as well as highthroughput molecular analyses to define and characterise the different immune cell populations
involved. Together with the Svensson laboratory, we will use a clinically relevant animal model to
examine the epigenetic profile of resident microglia. And finally, the Svensson and Baron laboratories
will use in-depth patient phenotyping and human tissue samples to generate translationally relevant findings.
Our work will not only yield a much deeper understanding of the CNS neuroimmune response in
chronic pain, but also has the potential to reveal novel upstream mediators and biomarkers that may
help identify who will be at risk of developing a chronic pain condition. Crucially, it may therefore bring
us one step closer to the elusive goal of adequately treating patients and thus greatly increasing their
quality of life.
of the condition is progressing, adequate therapies are still lacking and millions of people are living
with persistent, debilitating pain that has no discernable function.
One of the most promising developments in recent years has been the recognition that microglial
activation is a key driver of neuropathic pain. This unexpected role of neuroinflammation brings us
tantalizingly close to potential new drug treatments. However, in order to translate this potential, we
need answers to several key questions.
First and foremost, which cells are driving chronic pain? The contribution of infiltrating monocytes versus resident microglial cells is unknown. Resolving this issue is a critical first step to target the
neuroinflammatory process. A second key question is how exactly do resident microglia and infiltrating
monocytes respond in different pain states? How do they mediate pro-inflammatory (and possibly antiinflammatory)
cascades? And over what time courses? Are they able to maintain an epigenetic, molecular memory of previous insults, which might then 'prime' them to drive a chronic pain state?
The aim of our proposal is to seek answers to these questions. A vital and obligatory step, if we hope
to develop novel analgesic strategies directed at spinal neuroinflammatory processes.
We are bringing together three laboratories, each with highly-specialised expertise that will enable a unique synergy. In the McMahon laboratory, we will use novel cell sorting techniques as well as highthroughput molecular analyses to define and characterise the different immune cell populations
involved. Together with the Svensson laboratory, we will use a clinically relevant animal model to
examine the epigenetic profile of resident microglia. And finally, the Svensson and Baron laboratories
will use in-depth patient phenotyping and human tissue samples to generate translationally relevant findings.
Our work will not only yield a much deeper understanding of the CNS neuroimmune response in
chronic pain, but also has the potential to reveal novel upstream mediators and biomarkers that may
help identify who will be at risk of developing a chronic pain condition. Crucially, it may therefore bring
us one step closer to the elusive goal of adequately treating patients and thus greatly increasing their
quality of life.
People |
ORCID iD |
Stephen McMahon (Principal Investigator) |
Publications
Denk F
(2016)
Persistent Alterations in Microglial Enhancers in a Model of Chronic Pain.
in Cell reports
Fernandez-Zafra T
(2019)
Exploring the transcriptome of resident spinal microglia after collagen antibody-induced arthritis.
in Pain
James Nicholas D.
(2018)
Neuromodulation in the restoration of function after spinal cord injury
in LANCET NEUROLOGY
Lopes DM
(2017)
The Molecular Fingerprint of Dorsal Root and Trigeminal Ganglion Neurons.
in Frontiers in molecular neuroscience
Lopes DM
(2017)
Sex differences in peripheral not central immune responses to pain-inducing injury.
in Scientific reports
Description | Latent enhancers - a novel mechanism for pain chronification? |
Amount | £447,885 (GBP) |
Funding ID | MR/P010814/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 08/2017 |
End | 08/2020 |
Description | NGN-PET (IMI2 call) |
Amount | € 1,500,000 (EUR) |
Funding ID | 116072 |
Organisation | European Commission |
Department | Innovative Medicines Initiative (IMI) |
Sector | Public |
Country | Belgium |
Start | 04/2017 |
End | 05/2020 |
Title | Flow cytometry protocol for human CSF |
Description | As part of this grant, the consortium has developed a flow cytometry protocol for human CSF. We also worked together to come up with improved FACS protocols for microglia derived from mice. |
Type Of Material | Technology assay or reagent |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | These protocols are difficult to set up, particularly the one concerning human CSF: the cells need to be processed within 2h of harvesting and numbers are an issue. Having a working method is going to be eminently useful going forward, since it will allow us to use human CSF from other patient groups to answer many other future research questions. It is the collaborative nature of ERA-NET that made this possible, since it brought together relevant ideas and unique expertise from the Karolinska Institute (who are flow experts), the University of Kiel (who have access to relevant patient groups) and our department (who came up with the flow cytometry panel). |
Title | RNA-seq and ChIP-seq datasets |
Description | We have generated several RNA-seq and ChIP-seq datasets as part of this grant, some of which have already been made publicly available. |
Type Of Material | Database/Collection of data |
Year Produced | 2016 |
Provided To Others? | Yes |
Impact | RNA-seq data in particular are very relevant for other research groups, as they can use them look up the expression level of their favourite genes. |
URL | https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE71136 |
Description | ERA-NET Kiel |
Organisation | University of Kiel |
Country | Germany |
Sector | Academic/University |
PI Contribution | The grant we obtained was in conjunction with two research laboratories - one in Kiel, Germany, and one in Stockholm, Sweden. It is a full collaboration, where each research lab has their own significant funds assigned to work on one project jointly. We are providing expertise in molecular biology and sequencing, as well as animal models of neuropathy. |
Collaborator Contribution | Kiel will provide invaluable clinical expertise, quantitative clinical data and patient tissue. |
Impact | This is a multidisciplinary collaboration. |
Start Year | 2015 |
Description | ERA-NET Stockholm |
Organisation | Karolinska Institute |
Country | Sweden |
Sector | Academic/University |
PI Contribution | The grant we obtained was in conjunction with two research laboratories - one in Kiel, Germany, and one in Stockholm, Sweden. It is a full collaboration, where each research lab has their own significant funds assigned to work on one project jointly. We are providing expertise in molecular biology and sequencing, as well as animal models of neuropathy. |
Collaborator Contribution | Stockholm will provide access to models of rheumatoid arthritis pain as well as patient material. |
Impact | This is a multidisciplinary collaboration. We are currently working on the submission of a joint manuscript concerned with RNA-seq of microglia in a mouse model of rheumatoid arthritis. |
Start Year | 2016 |
Description | Cell Reports Paper |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Public/other audiences |
Results and Impact | We issued a press release on our latest paper, which was picked up by the Daily Mail and the Washington Post. |
Year(s) Of Engagement Activity | 2016 |
URL | http://www.dailymail.co.uk/health/article-3587283/Why-DOES-chronic-pain-exist-Scientists-agony-persi... |