Inflammatory pain and hyperalgesia are considered functional features of an immune response, intended to protect tissue from further damage. At the affected site, immune cells and inflammatory mediators activate sensory neurons, resulting in pain signalling. The general consensus asserts that this pain passively resolves following cessation of the inflammatory stimulus. However, in many patients with chronic inflammatory diseases (such as rheumatoid arthritis and inflammatory bowel disease), resolution of inflammation does not translate to cessation of pain. This subsequently leads to chronic pain, where pain signals remain active for weeks to years, severely impacting a patient’s quality of life. The mechanism by which inflammatory pain is successfully resolved remains poorly understood.
Researchers in the Netherlands have discovered a novel mechanism by which macrophages contribute to pain resolution in mice (https://doi.org/10.1101/2020.02.12.940445). Macrophage accumulation was observed at the site of induced inflammatory pain, while levels of T cells, B cells or other CD45+ immune cells in the affected area did not change significantly. It has been previously demonstrated that a deficiency in mitochondrial function in sensory neurons prevents the resolution of inflammatory pain; thus, it was interesting to observe that macrophages dynamically controlled the resolution of pain from the site of inflammation by transporting mitochondria to sensory neurons, thereby restoring the neuronal metabolic balance.
During the pain resolution process in mice, M2-like macrophages penetrate the dorsal root ganglia (where the somata of sensory neurons are situated). This process is simultaneous with the recovery of oxidative phosphorylation in sensory neurons. Using flow cytometry, it was found that macrophages released CD45+ extracellular vesicles containing macrophage plasma membrane proteins. This transfer involved the expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons.
These findings may lead to new strategies in pain management, which may focus on the restoration of metabolic homeostasis in neurons or on increasing transfer of mitochondria from macrophages. Synexa Life Sciences has extensive experience in flow cytometric characterisation of macrophages and their receptors, as well as in the functional assessment of immune cells. In addition, cell culture specialists at Synexa Life Sciences are developing a three-dimensional in vitro cellular model, that will allow for the assessment of the influence of specific immune cells on neuronal integrity, signalling and the microenvironment.