Exactly how asthma begins and progresses remain a mystery, but a team of researchers has uncovered a fundamental molecular cue that the nervous system uses to communicate with the immune system, and may potentially trigger allergic lung inflammation leading to asthma. Their insights into this neuro-immune crosstalk are published in Nature.
"Our findings help us understand how the nervous system is communicating with the immune system, and the consequences of it," said co-senior author. "What we're seeing is that neurons in the lungs become activated and produce molecules that convert immune cells from being protective to being inflammatory, promoting allergic reactions."
The research team closely examined lung-resident innate lymphoid cells (ILCs), a type of immune cell that can play a role in maintaining a stable environment and barrier in the lungs, but can also promote the development of allergic inflammation. Using a technique known as single-cell RNA sequencing, the team explored more than 65,000 individual cells that exist under normal or inflammatory conditions, looking for genes that were more active in one state or subpopulation versus another.
"By surveying thousands of individual cells, we were able to define the transcriptional landscape of lung-resident ILCs, observing changes in discrete subpopulations," said another author.
Among many distinguishing genes they found, one in particular stood out: Nmur1, a receptor for the neuropeptide NMU. In laboratory and animal model experiments, the team confirmed that NMU signaling can significantly amplify allergic inflammation when high levels of alarmins - molecules known to trigger immune responses - are present.
The team also observed that ILCs co-located with nerve fibers in the lung. Neurons in the lung can induce smooth muscle contractions that manifest themselves as coughing and wheezing, two central symptoms of asthma.
"Coughing is something regulated and controlled by the nervous system so it's intriguing that our findings point to a role for NMU, which can induce both smooth muscle contraction and inflammation," said the author.
Interestingly, two additional Nature papers released simultaneously revealed that ILC2 cells in the gut also express Nmur1, take on an inflammatory state when exposed to NMU, and live in close proximity to NMU-producing nerve cells.
"We anticipate that the NMU-NMUR1 pathway will also play a critical role in amplifying allergic reactions in the gut and promote development of food allergies," said the author.
In addition to uncovering a novel neuro-immune pathway that leads to inflammation, the team also hopes their findings will lead to new therapeutic insights for how to potentially prevent or treat allergic asthma.
"We may have identified a way of blocking allergic lung inflammation by controlling neuropeptide receptors," said the authord. "This work represents a mechanistic insight that could lead to the development of a new therapeutic approach for preventing asthma."
Neuro-immune crosstalk in allergic asthma
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