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Newly Discovered Cell Type May Lead to Targeted Therapies for Chronic Neuropathic Pain

Spinal macrophages may limit neuroinflammation, resolve mechanical pain, and dampen anti-inflammatory response after injury. Plus, they offer an alternative to opioids.

A PPM Brief with Mark Zylka, PhD

Peripheral nerve injury can cause an inflammatory response in the spinal cord, leading to chronic neuropathic pain. As pain specialists know, pinpointing the cause of the pain can be difficult.

Treating chronic neuropathic pain poses a variety of challenges, not the least of which is managing the risks of opioid therapy, which is often necessary for this kind of intractable pain. However, a recent discovery made by researchers at the University of North Carolina suggests that a clearer understanding of  the cellular mechanisms involved in the inflammation associated with neuropathic pain might lead to better therapies for this disabling condition.

Targeted expression of Cd163 increased spinal macrophage production resulted in enduring resolution of pain. (Image: iStock)

Anti-Inflammatory Macrophages Attack Nerve Inflammation and Pain

In a study published in March 2021 in Neuron, researchers from the University of North Carolina School of Medicine discovered a class of anti-inflammatory macrophages that, when activated, can reduce pain caused by nerve damage.1 The problem – even irony – is that neuropathic pain can disable these cells, the very cells that might help reduce the inflammation and, thus, the pain. However, the researchers were able to reactivate these cells, suggesting the possibility of novel treatments for chronic neuropathic pain. 

The discovery was made possible using an emerging technology called single-cell RNA-sequencing. This technique allows scientists to look at thousands of cells at once, locate rare cell populations, and track the changes in those cells. The UNC team used this technology to determine which spinal cell types respond or fail to respond during chronic pain following nerve injury. 

The team performed single-cell RNA sequencing on spinal cord segments of adult male mice 14 days after spinal injury. Using the spared nerve injury (SNI) model of neuropathic pain, they recovered approximately 10,000 cells from sham surgery controls and approximately 9,000 cells from SNI mice. They also detected 66 spinal cell sub-types, which were categorized into several principal cell types. Next, they compared the changes in cell proportions between the mice with spinal cord injuries and the animals with sham injuries to investigate the differences in the cells during neuropathic pain. Further analyses using functional Gene Ontology provided additional insights into how the spinal macrophages responded after a nerve injury.

The UNC researchers found that MRC1+ macrophages are activated in animals (mice) with nerve injuries. In their animal models, these cells up-regulated Cd163, an anti-inflammatory mediator, following superficial injury (sham injury). The macrophages both increased in number and Cd163 expression – which was expected. The surprising finding was that the activation was blunted in nerve-injured animals relative to the sham-injured controls.

“Our data indicate that the MRC1+ spinal macrophages actively… limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response,” the study authors wrote.1

Although the study did not examine the mechanisms that prevented the macrophages from being fully activated, the researchers did discover that the cells were not permanently disabled. The team was able to induce the macrophages to increase their anti-inflammatory response by injecting nanoparticles into the spinal cords of the mice. These nanoparticles were loaded with Cd163 expression plasmid. Control mice were given an empty vector. The results indicate, “that targeted elevation of Cd163 in MRC1+ spinal macrophages in neuropathic animals can resolve neuroinflammation and attenuate mechanical hypersensitivity.”1

Indeed, the team found that targeted expression of Cd163 increased spinal macrophage production and resulted in enduring resolution of pain.

Neuropathic Pain and Potential New Therapies

Overall, these findings suggest that boosting the anti-inflammatory macrophages could lead to new therapies for neuropathic pain and, possibly, inflammatory pain as well.

“Our data indicate it is possible to reactivate the macrophages and make them more anti-inflammatory,” senior author of the study Mark Zylka, PhD, director of the UNC Neuroscience Center and Kenan Distinguished Professor of Cell Biology and Physiology, told PPM.

“We are taking several approaches to turn this basic science discovery in mice into a therapy for humans.” While it is still unknown if these potential therapies would have any significant side effects, Dr. Zylka points out that “these therapies do not engage the opioid system, so none of the serious side effects associated with opioids are expected.”

The researchers noted one caveat about their findings. They were done on only male mice. Because  inflammatory processes that lead to pain can differ in males and females, future studies will be needed to determine if these macrophages operate similarly in females.

Last updated on: April 9, 2021
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