Abstract
At first sight chronic pain might seem a pure neurological problem. However, evidence indicates that the immune system contributes in pain pathways. In this thesis, the focus was on elucidating the role of macrophages in 1) transient inflammatory pain where endogenous resolution pathways are active, and 2) chronic osteoarthritis (OA) pain, a pathophysiological condition where pain resolution fails. By understanding how resolution of transient pain is regulated, and learning what goes wrong during chronic pain, we aim to identify highly needed novel options to treat chronic pain.
In this thesis, macrophages were identified as key regulators of pain and that these cells control pain remotely from the site of inflammation or damage. We identified that macrophages, particularly those with the M2 phenotype, control the resolution of pain in a transient inflammatory pain model by a previously unrecognised mechanism, independent of their cytokine release. On the other hand, we showed in a persistent osteoarthritis pain model that macrophages, in this case with the M1 phenotype, have a completely different function and maintain pain. Finally, by inhibiting M1 macrophages in the DRG persisting OA pain was suppressed, indicating that targeting these macrophages is a potential therapeutic approach to treat debilitating pain conditions.
In chapter 2, the role of immune cells and their mediators in regulation of pain is reviewed and evaluated. Here we identified, based on what was already known, that the immune and nervous system closely interact, and that immune cells have important but distinct roles in regulating different types of pain. In chapter 3, we showed macrophages accumulate in the dorsal root ganglia during the resolution of inflammatory pain and acquire a M2-like phenotype. To resolve pain, macrophages transfer functional mitochondria in vesicles to DRG sensory neurons. This transfer requires expression of CD200R on vesicles released by macrophages and the CD200R-ligand iSec1 on neurons. In chapter 4, we investigated the role of macrophages in the regulation of persistent OA pain. We unravelled that during the course of OA, macrophages accumulate in the DRG innervating the damaged OA affected knee, and acquire a M1-like phenotype and maintain OA pain. Importantly, these DRG macrophages maintain pain independent from the damage of the knee joint. Finally, inhibition of DRG macrophages, controlled OA pain. In chapter 5, we identified CXCL11 as a main driver for the accumulation of DRG macrophages in OA. However, despite their presence very early during the initiation of OA pain, these DRG macrophages are not required for the initiation of pain. CXCL11 is required to attract macrophages to the DRG but not sufficient to program these DRG macrophages into a pain maintaining phenotype.
Altogether, in this thesis we elucidated unprecedented roles of macrophages in the regulation of pain. DRG macrophages can have pain promoting or pain resolving functions depending on their phenotype that are likely governed by the DRG milieu. Finally, we showed that in case of chronic pain targeting the polarized DRG macrophages gives an opportunity for novel therapeutic strategies to potentially treat variety types of chronic pain.
In this thesis, macrophages were identified as key regulators of pain and that these cells control pain remotely from the site of inflammation or damage. We identified that macrophages, particularly those with the M2 phenotype, control the resolution of pain in a transient inflammatory pain model by a previously unrecognised mechanism, independent of their cytokine release. On the other hand, we showed in a persistent osteoarthritis pain model that macrophages, in this case with the M1 phenotype, have a completely different function and maintain pain. Finally, by inhibiting M1 macrophages in the DRG persisting OA pain was suppressed, indicating that targeting these macrophages is a potential therapeutic approach to treat debilitating pain conditions.
In chapter 2, the role of immune cells and their mediators in regulation of pain is reviewed and evaluated. Here we identified, based on what was already known, that the immune and nervous system closely interact, and that immune cells have important but distinct roles in regulating different types of pain. In chapter 3, we showed macrophages accumulate in the dorsal root ganglia during the resolution of inflammatory pain and acquire a M2-like phenotype. To resolve pain, macrophages transfer functional mitochondria in vesicles to DRG sensory neurons. This transfer requires expression of CD200R on vesicles released by macrophages and the CD200R-ligand iSec1 on neurons. In chapter 4, we investigated the role of macrophages in the regulation of persistent OA pain. We unravelled that during the course of OA, macrophages accumulate in the DRG innervating the damaged OA affected knee, and acquire a M1-like phenotype and maintain OA pain. Importantly, these DRG macrophages maintain pain independent from the damage of the knee joint. Finally, inhibition of DRG macrophages, controlled OA pain. In chapter 5, we identified CXCL11 as a main driver for the accumulation of DRG macrophages in OA. However, despite their presence very early during the initiation of OA pain, these DRG macrophages are not required for the initiation of pain. CXCL11 is required to attract macrophages to the DRG but not sufficient to program these DRG macrophages into a pain maintaining phenotype.
Altogether, in this thesis we elucidated unprecedented roles of macrophages in the regulation of pain. DRG macrophages can have pain promoting or pain resolving functions depending on their phenotype that are likely governed by the DRG milieu. Finally, we showed that in case of chronic pain targeting the polarized DRG macrophages gives an opportunity for novel therapeutic strategies to potentially treat variety types of chronic pain.
Original language | English |
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Award date | 11 Dec 2020 |
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Print ISBNs | 978-94-6416-251-6 |
DOIs | |
Publication status | Published - 11 Dec 2020 |
Keywords
- Macrophage
- Immune cells
- Inflammatory pain
- Osteoarthritis pain
- Pain resolution
- Sensory neurons
- Dorsal root ganglia
- CXCL11
- Mitochondria