My MSCA project aimed to define the role neuronal signals in the regulation of innate immune cells known to be involved in the progression of various inflammatory diseases such as asthma, allergy or parasitic infection.
Innate lymphoid cells (ILC) were discovered very recently, in 2008, but they are very ancient in evolutionary terms. They are divided in 3 groups in function of their physical and functional criteria. Among them, ILCs type 2 produce substances that are essential to immune responses against parasites or allergens (such as dust mite). These cells are normally abundant at barrier sites, such as the gut, lungs and skin, which serve as physical fortresses to the body.
Most neurons in the body are located in the brain and its vicinity – the central nervous system –, with neurons projecting their axons to every tissue in the organism by way of the spinal cord. In turn, glial cells are neuron satellites ensuring the cohesion of the nervous tissue. Nevertheless, throughout the body there is a very abundant number of peripheral nervous cells. These are so numerous in the gut that they have collectively been dubbed “the second brain”. What do these peripheral nervous cells do? they are in fact extremely important for the organism to be able to mount adequate immune responses and preserve health.
During my MSCA, we have revealed that these immune cells would not be able to develop their protective actions against infections without establishing a “dialog” with neurons residing at those sites. In fact, neurons located at mucosal tissues can immediately detect an infection in the organism, promptly producing a substance that acts as an “adrenaline rush” for immune cells. Under the effect of this signal, immune cells rapidly become poised to fight the infection and repair the damage caused to surrounding tissues. We have published those results in Nature on Sept 6,2017.
How did we discover this neuro-immune tandem? We observed that ILC2s were placed along the axons of neurons residing in the mucosa. Thus, we wondered whether these two distinct tissues could productively ‘talk’ to each other. To test this hypothesis, we started by analyzing the whole genome of a series of immune cells–ILC1s, ILC2s, ILC3s, T-cells, etc.–searching for genes that code molecules that may act as receivers of neuronal signals. We that only ILC2s possessed a defined “receptor” (membrane molecules that act as antennae) for nervous signals. We notably discovered that ILC2s have receptors to a neuronal messenger called neuromedinU (NMU). Since neurons are the only cells that produce abundant NMU levels, this indicated that only neurons could be sending this signal to ILC2s. Then we wondered how this neuronal peptide regulate ILC2 in health and under inflammatory conditions. To answer this question, we used a rodent parasite, Nippostrongylus brasiliensis (a sort of hookworm) to infect “normal” control mice and mutant mice whose ILC2s had been stripped of their NMU receptors. In the first group of animals, the innate immune cells immediately triggered a response to neutralize the parasite and repair damaged tissue. In the second group, the mice were unable to fight the infection and the damage caused by the parasite –including the internal bleeding of the lungs due to N. brasiliensis. We also showed that neurons are able to detect the products secreted by parasites that infect the organism –and that, when this happens, they rapidly produce NMU. In turn, NMU acts vigorously on ILC2s, thus generating a protective response in a few minutes.
