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Pain Is an Effect of Inflammation But May Also Drive Immune Responses

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Pain is a signal for tissue damage that tells our brain something is wrong, and now, research suggests that pain and the neurons that detect it may also communicate with our immune system.

Researchers have found a surprisingly intricate connection between pain-sensing neurons and immune cells. It may help us understand important immune processes such as inflammation, which could be targeted for future treatments such as medicines that inhibit pain neurons from triggering an immune response.

In medicine, people typically think pain is a consequence of inflammation, said Ulrich von Andrian, professor of immunopathology, microbiology and immunobiology at Harvard Medical School. This research “suggests that pain can actually also be a driver of inflammation or at least a modulator of the inflammatory response.”

The study, which was conducted in mice, was published in the journal Science. It uncovered three different ways by which nociceptors, neurons that sense pain and itch, communicate and control immune cells in the skin.

“What it really shows is that inflammation and response to tissue damage or to infection, it’s not a sole response of the immune system,” said Sebastien Talbot, an associate professor of biomedical and molecular sciences at Queen’s University. “It also involves the nervous system.”

Future treatments that involve inflammation may need to take both the immune system and the nervous system into account, researchers said.

Von Andrian, an author of the study, became interested in how neurons could influence the immune system because of unusual observations doctors made in 1990 and 2005 about psoriasis patients.

Psoriasis is an autoimmune skin condition where immune cells attack the skin, creating lesions that often itch and burn, sensations transmitted by pain-sensing neurons.

The skin lesions are typically symmetrical — if they are on the left hand, they will probably also be on the right hand, for example. Twoclinicalreports, however, noted that in some patients, nerve damage in one limb caused them to lose sensation and psoriasis in that limb. As the nerves regenerated and sensation returned, though, so did the psoriasis.

As later corroborated in animal studies, the pain neurons seemed essential for the inflammatory responses.

How the neurons are communicating with the immune cells, however, remained a mystery. Until now.

Pain neurons tell immune cells to approach and stay close

Dendritic cells are the “guardians” of our immune system. They sit at our barrier tissues that separate our bodies from the outside world — our throats, mouths, gut and skin — “standing guard, like sentinels that are looking for invading pathogens that are not supposed to be there,” von Andrian said.

They have a close relationship to pain-sensing neurons — under the microscope, all dendric cells were always in contact with at least one nerve fiber. In animals, dendritic cells are on constant patrol; as the cells crawl along the neuron fibers, “it looks like a kid on the monkey bars,” von Andrian said.

The researchers discovered that this close contact is because the pain-sensing neurons release a chemical “find me” signal, called CCL2, which attracts dendritic cells from a distance “like a pheromone,” von Andrian said.

This signal also acts as a “stay here” cue, which gives dendritic cells time to gather intel about pathogen threats. When dendritic cells detect antigens from a pathogen (or vaccine), they rush off to the lymph nodes to activate the rest of the immune system.

When the researchers genetically engineered mice whose pain-sensing neurons did not make the chemical signal, “the dendritic cells hastily rush into the draining lymph vessels and go to the lymph node without actually having all the information that they need,” von Andrian said. “And then the immune response in the skin is compromised.”

Pain neurons enhance immune cells and send a ‘go’ signal

When we experience an injury, our pain sensors send signals to the brain so we can perceive pain, and do something about it.

At the same time, the pain neurons release neuropeptides, called calcitonin gene-related peptide (CGRP), which tell local dendritic cells to “get ready.” CGRP seems to reprogram dendritic cells to promote the expression ofgenes important for pathogen resistance and eating bacteria.

“It’s like a program that enhances their sentinel function,” von Andrian said. “They become better guardians of our peripheral area tissue.”

Dendritic cells then load themselves with inflammatory cytokines for a more potent effect, but this does not cause inflammation by itself. Instead, it waits for a “go” signal.

Pain and the electrical activity generated in the pain-sensing neurons provide this signal, a finding that shocked the researchers. The neurons conduct electrical signals, which somehow pass through into adjoining dendritic cells — the researchers are unclear on the mechanism. These electric signals, coupled with the presence of inflammatory molecules, tell dendritic cells to go.

“What I didn’t expect was that the dendritic cell would almost function like a neuron, and that it would actually not just somehow know that the nerve fiber iselectrically active, but it itself actually became electrically active,” von Andrian said.

The electrical communication between neurons and immune cells was an “unexpected finding, but really, really, really interesting,” and may allow more fine-tuning of immune responses, said Talbot, who also wrote a commentary summarizing the study.

Shifting paradigms and new treatment possibilities

The research shows both that pain can drive inflammation and that neurons can influence immune function.

These studies were conducted with mice because there are limits to the kinds of experiments we can feasibly and ethically perform in humans. While we don’t know whether the same processes occur in humans, the cell types and molecules involved are evolutionarily conserved and thought to function similarly in our bodies, the researchers said.

“I really anticipate that this would translate pretty well into humans,” said Talbot, who was not involved in the study.

Understanding how the nervous system influences the immune system creates opportunities to better control immune responses in patients where they go awry, though more research is needed.

“It creates a whole new paradigm where we could control immune responses in a variety of pathology,” Talbot said.

For example, CGRP, the get ready signal, is known to be involved in migraine, and there are drugs approved to inhibit the molecule.

Blocking the activity of the pain neurons with topical anesthetics such as lidocaine could help block the immune cell go signal, though the effects are not long-lasting. Pharmaceutical companies are also working to develop longer-lasting topical anesthetics, which may help in the future, Talbot said. (Painkillers would not work because they act on our pain perception in the brain and not on the pain-sensing neurons.)

“Neurons communicate with immune cells with many more signals than we thought,” Talbot said. “In this case, they look at," one "side of the equation, where neurons activate the immune cells. But it’s also known that the immune cells activating neurons is really important to drive chronic pain. So it’s kind of the yin and the yang of the equation.”

Do you have a question about human behavior or neuroscience? Email and we may answer it in a future column.

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Schedule17 Jun 2024