Pain sensing neurons in the gut kindle inflammatory immune responses that cause allergies and asthma, according to a new 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," said senior author Dr. David Artis , director of the Jill Roberts Institute for Research in Inflammatory Bowel Disease and the Michael Kors Professor in Immunology at Weill Cornell Medicine.
While the idea may be new to the field, Dr. Artis has been thinking about the role the nervous system may play in allergies and asthma for about two decades. For example, many of the symptoms that characterize these conditions, like itching and wheezing, are known to be neuronally controlled. "That was one of the clues that prompted us to look closer for a connection," Dr. Artis said.
Insights from the Immune Response to a Parasite
The same type of immune reaction triggered by allergens is also triggered by parasitic worms, providing a convenient tool for the researchers to leverage. They infected mice with an intestinal worm called Trichuris muris, then examined 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, such as the compound capsaicin, which gives chili peppers their heat, making it plausible that they also sense allergens.
The researchers found that Trichuris muris did activate nociceptors, which then kicked off an immune response. Nociceptors send signals to a subset of the cells lining the gut called tuft cells, which then send out parasite-fighting immune molecules. The neurons do this by releasing a molecule called CGRP, which signals to tuft cells to activate.
With finger-like protrusions that extend into the intestinal tract, tuft cells are key to fighting off parasites. "They're not a classical immune cell type, but their role in the reaction to parasites is crucial," said Elizabeth Emanuel, a Weill Cornell Medicine Graduate School of Medical Sciences doctoral candidate in the Artis lab and a co-first author on the publication. This partnership not only helps clear parasites but also reshapes the gut lining to prepare for future threats.
So crucial, in fact, 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, the researchers found by adopting a cutting-edge technique called spatial transcriptomics to gain an inside view into how individual cells in the gut react to nociceptor activation at a genetic level.
When they 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," said Dr. Wen Zhang, instructor of immunology in medicine at Weill Cornell Medicine, and a co-first author on the study. 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. This study offers clues to similar mechanisms that may underlie airway diseases like asthma.
"That's a textbook-changing concept that we're studying," Dr. Zhang said. "We've traditionally thought that type 2 immune responses are initiated through coordinated interactions between epithelial and immune cells, but our findings reveal an unexpected role for the nervous system in launching this response."
If the same neuronal-immune cell axis found in mice is also present in humans, it could explain some puzzling characteristics of allergic reactions, including why intestinal cramps are often a very early sign — occurring before there's evidence that the immune system has been activated.
Emanuel can envision translating the findings into humans by using patient biopsies to look for activation of the same cell types. "That could be an interesting opportunity to move these findings closer to new therapeutic interventions," she said.
Dr. Artis hopes the realization that nociceptors kick-start immune reactions will help pharmaceutical companies fill in the gaps left by current treatments for allergies and asthma. "Perhaps the next generation of therapeutics might target both the immune system and the nervous system for more effective control," he said.
