The release of a protein called HMGB1 from neurons can cause inflammation, according to a study published August 17 in PNAS. The researchers say this shows that neurons play an important role in initiating the immune response to injury and infection, and ushers in new ways of treating otherwise drug-resistant kinds of pain. 

“There are a lot of cells that theoretically could use HMGB1 and probably do use HMGB1 for signaling. What’s interesting is that it’s involved in the nervous system,” notes David Pisetsky, an immunologist at the Duke University School of Medicine in North Carolina who studies the protein but was not involved in the new work. Pisetsky says he also thinks the result portends an increased focus on nerves for reducing immune-related pain.   

Inflammation—an immune response characterized by heat, pain, redness, and swelling—helps the body repair tissues after infection or injury, as it assists with removing whatever caused cells to be harmed along with any cell debris. However, prolonged or inappropriate inflammation can cause lasting damage and result in chronic pain, so researchers are keen to uncover ways to tamp down on inflammation in people with intractable pain.  

Previous studies have established that immune cells release high mobility group box protein 1 (HMGB1) to kick off an inflammatory response, but HMGB1 is also present in almost all cells because it plays an important role in DNA transcription. That could mean a variety of cells can trigger inflammation, so the research team—led by biochemist Huan Yang at Northwell Health’s Feinstein Institutes for Medical Research in New York—decided to investigate whether sensory neurons, which are key sentinels for tissue damage, also use the protein to mobilize an immune response.  

Yang used mice engineered to have sensory neurons with a blue light-sensitive ion channel. She then harvested the neurons and stimulated them with blue light for 30 minutes, and found that the neurons released HMGB1 in the hours following. Neurons that were exposed to a nonstimulating yellow light instead did not release HMGB1 over the same time period. In separate experiments, mice engineered to lack HMGB1 experienced less inflammation and reduced sensitivity to pain than controls when given a sciatic nerve injury or arthritis. 

From these findings, the team concluded that “neurons can release molecules that spark an inflammatory response,” Yang says—and if that’s the case, then targeting neurons could be a novel way of dampening inflammation and inflammatory pain. 

While there are already treatments available for inflammation-driven conditions such as rheumatoid arthritis, some people don’t respond to these treatments, notes Sangeeta Chavan, a coauthor on the paper. Yang and Chavan both work in Northwell Health’s bioelectronic medicine division, which aims to develop devices that modulate the activity of the nervous system without requiring drugs. Chavan says that developing bioelectronic treatments that inhibit HMGB1 expression could help people with autoimmune conditions or nerve injuries who have limited treatment options today. 

“The fact that you can use a blue light to change the way that cells respond, as a conceptual way to modulate pain control—to me that’s more the big splash here,” says Fletcher White, a neuroscientist at the Indiana University School of Medicine who studies the role of HMGB1 in lingering pain induced by chemotherapy drugs and was not involved in the study.  

According to White, using bioelectronic techniques to manage pain instead of drugs has real therapeutic potential, especially given the fact that the opioids often employed to control pain are highly addictive. 

Pisetsky agrees—in principle. “We don’t have that many good targets for pain. Time will tell whether [HMGB1] is a good target,” he says.