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

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.

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.