Pain-Sensing Neurons Kick-Start Immune Responses

Pain-sensing neurons in the gut kindle inflammatory immune responses that cause allergies and asthma, according to a recent study by Weill Cornell Medicine. The findings, published Jan. 7 in Nature, suggest that current drugs may not be as effective because they only address the immune component of these conditions, overlooking the contribution of neurons.

“Today’s blockbuster biologics are sometimes only 50% effective, and when the treatments do work, they sometimes lose their efficacy over time,” says senior author Dr. David Artis.

Because the same type of immune reaction triggered by allergens is also triggered by parasitic worms, researchers used models infected with an intestinal worm called Trichuris muris to examine the activity of nociceptors, neurons that have specialized nerve endings throughout the body and transmit pain and itching signals to the brain. Nociceptors sense irritants, making it plausible that they also sense allergens.

The researchers found that Trichuris muris did activate nociceptors, which then released a molecule called CGRP, kicking off an immune response. The nociceptors signal to a subset of cells lining the gut called tuft cells that send out parasite-fighting immune molecules.

With fingerlike protrusions extending into the intestinal tract, tuft cells are key to fighting off parasites. They are so crucial that another function of the nociceptor sensory neurons is to release chemical signals that cause a separate group of epithelial cells to morph into additional tuft cells. This partnership not only helps clear parasites but also reshapes the gut lining to prepare for future threats.

When the researchers used a technique called immunofluorescence microscopy to visualize the epithelial changes in response to nociceptor activation, they observed a striking and rapid population expansion of tuft cells. Within just 24 hours of neuronal activation, tuft cell numbers increased by nearly fivefold.

“That seems to be a key strategy that pain-sensing neurons use to enable a fast, efficient response to parasites,” says co-first author Dr. Wen Zhang. On the other hand, when these neurons are silenced or removed, tuft cell numbers decrease and the gut struggles to fight the infection.

The inflammatory immune responses are essential for fighting parasites and repairing tissue, but when they become chronic or excessive, they can drive allergic diseases such as asthma and fibrosis. The same cellular pathways that clear intestinal parasites through tuft cells might also fuel allergic inflammation in the lungs and other tissues. The study offers clues to similar mechanisms that may underlie airway diseases like asthma.