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Impact of Neuromedin U in type 2 immunity and mucosal defence

Periodic Reporting for period 1 - INIMUD (Impact of Neuromedin U in type 2 immunity and mucosal defence)

Reporting period: 2017-07-01 to 2019-06-30

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.
Group 2 innate lymphoid cells (ILC2s) regulate inflammation, tissue repair and metabolic homeostasis, and are activated by host-derived cytokines and alarmins. Discrete subsets of immune cells integrate nervous system cues, but it remains unclear whether neuron-derived signals control ILC2s.
My MSCA project aimed to understand how neurons regulates ILC2 in healthy and pathological conditions. We showed that neuromedin U (NMU) in mice is a fast and potent regulator of type 2 innate immunity in the context of a functional neuron–ILC2 unit. We found that ILC2s selectively express neuromedin U receptor 1 (Nmur1), and mucosal neurons express NMU. Cell-autonomous activation of ILC2s with NMU resulted in immediate and strong NMUR1-dependent production of innate inflammatory and tissue repair cytokines. NMU controls ILC2s downstream of extracellular signal-regulated kinase and calcium-influx-dependent activation of both calcineurin and nuclear factor of activated T cells (NFAT). NMU treatment in vivo resulted in immediate protective type 2 responses. Accordingly, ILC2-autonomous ablation of Nmur1 led to impaired type 2 responses and poor control of worm infection. Notably, mucosal neurons were found adjacent to ILC2s, and these neurons directly sensed worm products and alarmins to induce NMU and to control innate type 2 cytokines.
Our work revealed that neuron–ILC2 cell units confer immediate tissue protection through coordinated neuroimmune sensory responses. Champalimaud Foundation (CF) contributed actively to the success of the project via their established Flow Cytometry, Rodent, Microscopy and Glass wash & media preparation platforms). With the help of the qualified personal at CF, I acquire new technical skills in flow cytometry, animal experimentation and microscopy. CF also allowed me to improve my communication skills by giving the chance to present my work at internal meetings and the Symposium.
Our work has been published in Nature. After publication, I had the chance to present my work in individual lab meetings and national and international congress, notably:
• ILC2018, Tokyo, Japan 2018–Best award poster
• Champalimaud Symposium, Lisbon, Portugal 2018–Poster
• ART congress, Sociéte française d’allergologie (SFA), Paris, France 2019–Invited talk
Regarding the outreach activities, our work was published in Ar Magazine and Publico (a daily national newspaper published in Portugal)
To summarize, this project was fundamental for my training in scientific and transferable skills, for enhancing contact networks for me and the host institution through academic conferences and public engagement events. All the results obtained with this Marie Sklodoska-Curie project contributed to increase the knowledge of ILC biology, as virtually very few was known about their neuronal regulation. Understanding regulation of ILC is of high importance for the development of new therapies for diseases where those cells have been previously described.
INIMUD contributed to the existing body of knowledge on the cross-talk between the mucosal nervous system and the immune cells and its role in the local tissue regulation. We newly identified Neuromedin U as a new linker between neuronal sensing, innate type 2 responses and mucosal protection.
Our discoveries have led to the creation of the company LiMM Therapeutics that harness the potential of neuronal regulators of ILCs (NRILs) to tackle unmet medical needs. LiMM is exploring a new paradigm in immune regulation, in which neuroregulators can potently activate multi-cellular units to confer local immune-mediated tissue protection. LiMM proposes the use of the neuropeptide NmU to shift the immune response towards an immune-mediated tissue protective response that prevents the development and/or halts the progression of inflammatory diseases such as obesity, asthma/allergy, atopic dermatitis.
This image shows by microscopy ILC2 in close proximity to the neurons in the intestine.