It is widely known that macrophages have a primary role of consuming pathogens and debris within cells, but there might be other important functions they fulfill.
Researchers in the Netherlands have identified other roles of macrophages, such as repair of damaged tissue and regulation of inflammation and pain [Raoof, R.; van der Vlist, M.; Willemen, H., et al. Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. bioRxiv Mar 2020; doi.org/10.1101/2020.02.12.940445].
Shuttling of mitochondria by macrophages to sensory neurons that supply inflamed tissue might help with resolution of pain.
The study was based on the induction of temporary inflammation in paws of mice through injection of carrageenan. Increased numbers of macrophages were found in close proximity to sensory neurons in the affected paws.
Previous experiments identified the association of chronic pain with reduction or depletion of monocytes (precursors to macrophages) and macrophages, or with mitochondrial defects. Inflammation might cause mitochondria to function less efficiently, and the replacement of new mitochondria is critical to improve cell function of the neurons.
To test this theory, the research team treated macrophages in culture with a mitochondria-specific stain, then added mouse neuronal cells. Within two hours, the stained mitochondria from the macrophages were found within the nerve cells.
The trial was also performed in live mice with similar results—increased numbers of stained mitochondria were observed in paws with inflammation.
Macrophage numbers returned to baseline levels once inflammation in the mouse paws resolved.
This led to experiments to see how macrophages could release mitochondria as packages contained in extracellular vesicles.
The researchers identified receptor CD200R that enable vesicles to dock onto sensory neurons via ligand-receptor interactions. It is theorized that sensory neurons with deficient mitochondria release signals to attract monocytes from surrounding blood. The monocytes then differentiate into macrophages that provide fresh mitochondria to neurons of inflamed tissue.
The team of scientists explain that inflammation results in a high energy demand for constant firing of action potentials, calcium signaling and maintenance of resting potentials. Such energy-consuming processes could drain energy supplies of nerve cells with damaged mitochondria, so fresh and effective mitochondria are needed within sensory nerves to handle the stress and energy demand crated by inflammatory pain.
Other research has demonstrated that macrophages release specific cytokines to manage inflammation perceived by sensory neurons.
The researchers suggest: “Functional mitochondria, but not their individual components, are sufficient to resolve pain.”
Additional studies are necessary to prove if mitochondrial function increases after their transfer into sensory neurons and that this is what helps to resolve pain.