A New Link Between Pain and the Immune System

Recent findings in mice show that cells called nociceptors contribute to the immune response after lung infection. Image credit: Patrick J. Lynch, medical illustrator (CC BY 2.5 [https://creativecommons.org/licenses/by/2.5]), via Wikimedia Commons.

There is a growing awareness among pain researchers that communication between the nervous system and the immune system contributes to pain. A recent animal study provides another interesting example of this phenomenon, by highlighting a previously unrecognized role for nociceptors in the immune response to bacterial lung infections.

Nociceptors are the nerve cells that detect potentially harmful things in the environment like excessive heat or dangerous chemicals, and relay information about those threats into the spinal cord and up to the brain, ultimately culminating in an experience of pain.

The study, led by Isaac Chiu at Harvard Medical School in Boston, shows that nociceptors that contain a protein called TRPV1 control the immune response, in the lungs of mice, against a lethal strain of bacteria called methicillin-resistant Staphylococcus aureus (MRSA). MRSA is a multidrug-resistant bacteria that causes respiratory tract infections, including pneumonia.

These nociceptors suppressed the activity of two different types of immune cells critical for the immune response to infection. And, removing the nociceptors from mice increased the survival of the animals when they were infected with MRSA. This experimental manipulation also helped the mice rid their lungs of bacteria.

“What is most striking about this paper is the somewhat unexpected role that nociceptors play in pulmonary [lung] host defense,” says Marzia Malcangio, of King’s College London, UK, who was not involved in the new study. Host defense refers to the immune response that animals mount to fight off foreign invaders like bacteria and protect against disease.

The findings were published in May in the journal Nature Medicine.

A direct impact
The lungs contain many nociceptors that are responsible for the coughing, shortness of breath and chest pain that accompany respiratory tract infections. Researchers had long assumed that bacterial infections lead to pain because inflammation that occurs during the immune response activates the nociceptors.

However, early on in his research career, Chiu discovered that bacteria could directly activate these nociceptors, independently of inflammation and the immune system response. Even more surprising, perhaps, was his discovery that experimentally manipulating mice so that they lacked certain types of nociceptors improved the animals’ immune response, and boosted their survival rates after infection.

This suggested an idea: maybe the nociceptors were somehow impairing the activation of immune cells in response to bacterial infection.

Building upon this work, Chiu and his colleagues turned their attention to the role that nociceptors in the lungs may play during lung infections, particularly pneumonia.

“As our background was in bacteria,” Chiu says, “we decided to concentrate primarily on bacterial infections.”

Testing a hypothesis
So the researchers got rid of the TRPV1-containing nociceptors in mice, using either genetic engineering or chemicals. Then they injected the animals with a lethal dose of MRSA, and saw how they fared compared to normal mice. While 80% of normal mice died from the bacteria, most of the mice without the nociceptors survived.

It looked like these cells were playing an important role in the immune response to bacterial lung infections—but how? To learn more, the researchers looked at the infected lungs of the mice missing the nociceptors and found more immune cells, and fewer bacteria, in the animals, compared to normal mice.

And, the animals without the nociceptors showed changes in cytokines, which are small proteins involved in the immune response to infection. This showed that a strong immune response was underway. In particular, the team discovered that the lungs of the mice missing the nociceptors had more of a population of immune cells called gamma delta T cells.

The next step
So the team then wondered: What would happen if they removed these T cells in the mice missing the nociceptors? They found that the animals were no longer protected against pneumonia, nor did they live as long. It looked, then, like the nociceptors contributed to infection because of their impact on the T cells, which suppressed the immune system.

Additional experiments would show that this depended on a molecule called CGRP, which is made by the nociceptors. This raised the possibility that curbing the activity of CGRP might be a way to help guard against bacterial lung infections and pneumonia.

In favor of that idea, the researchers saw that a drug that limited the activity of CGRP in normal mice improved survival after they were exposed to MRSA. Here, though, Chiu says that CGRP is likely just one of many molecules that play a role in the fight against infection.

A more recent study from Chiu’s lab highlights another example of connections between the nervous system and immune system. The researchers found that the so-called “flesh-eating” bacteria, Streptococcus pyogens, directly activates the nociceptors. And, once again, dampening the activity of CGRP helped prevent and treat the infection.

To read about the research in more detail, see the related IASP Pain Research Forum news story here.

Dara Bree is a postdoctoral fellow at Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, US.