ERA-NET NEURON: Identification and study of different immune cell populations and their role in chronic pain

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.

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.

Publications

10 25 50
 
Description Latent enhancers - a novel mechanism for pain chronification?
Amount £447,885 (GBP)
Funding ID MR/P010814/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
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 Multiple
Country European Union (EU)
Start 05/2017 
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...