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Sensing Neuro-immune Activation in the Lung microenvironment

Periodic Reporting for period 1 - SIGNAL (Sensing Neuro-immune Activation in the Lung microenvironment)

Berichtszeitraum: 2020-04-01 bis 2022-03-31

SIGNAL, a Horizon 2020 MSCA project, seeks to understand how our neurons can affect the immune response in the context of mucosal immunity (e.g. in the lung, female reproductive tract…). We aim to develop experimental mouse models to investigate these interactions (neuro-immune crosstalk) and better comprehend whether a subgroup of our immune cells is specialized to translate neuronal-derived cues during immune responses. We focus on how the neuro-immune crosstalk participates in allergy and asthma.

While the scientific and medical communities have studied allergies and asthma for a long time, and have developed superior treatments for these pathologies, there is still much about the causes and prevalence of allergies that we do not understand. Stress can trigger asthma attacks, worsen allergies, and even promote autoimmune disorders. We still do not understand why or how this happens, but recent investigations are starting to reveal that the nervous system plays a pivotal role in controlling immune responses to pathogens and allergens. In some instances, our nervous system boosts the immune response and promotes inflammation, while in other cases it suppresses the immune system. We do not comprehend the mechanisms behind this discrepancy. We require precise knowledge of how the interaction between the immune and nervous systems affects our immunity in health and disease. Here is where SIGNAL tries to provide insight into this question: we want to contribute to understanding the neuro-immune crosstalk so eventually this knowledge translates into better management of immune-related pathologies.

The overall aims of the project are to develop technical tools and scientific pre-clinical laboratory models to study how the activation or inhibition of specific types of neurons influence the immune response during allergic reactions. SIGNAL intends to define how controlling distinct groups of neurons affects allergic inflammation in the lung. In addition, SIGNAL aims to investigate whether the input from neurons into the immune system affects all immune cells to a similar extent or whether some immune cells are specialized in sensing the cues derived from neurons. If we can identify immune cells that are dedicated to coordinate the neuro-immune crosstalk, we plan to study their biology.
During the time I have been working on SIGNAL, I have implemented several experimental approaches to study the interaction between the nervous system and the immune system (i.e. the neuro-immune crosstalk). I have established fruitful collaborations with other labs which have been critical to developing these methods. The COVID19 pandemic had a significant impact on the progress of the action, and it hindered the originally planned progression of the experiments. However, with the support of the host lab (Andrew McKenzie’s research group) and institution (MRC Laboratory of Molecular Biology), I managed to continue my work and grow as a scientist.

We established eight different models to implement in our experiments exploring the neuro-immune crosstalk: three drug-based methods, two transgenic models, two chemogenetic models, and one optogenetic approach. We acquired, established, and bred several new mouse strains to be able to manipulate various subtypes of neurons and study their influence on immune cells. We also developed completely novel transgenic mouse strains that will help to target a subset of neurons in the intestine. These mouse strains have been valuable in the investigations for SIGNAL but they are also being used in other projects in the host lab.

By combining the aforementioned approaches with mouse models of type-2 immunity (i.e. the class of immune responses implicated in allergy and asthma) we were able to start elucidating how the neurons were regulating these immune reactions. We confirmed that sympathetic neurons are inhibiting inflammation in the lung, while other subtypes of neurons are promoting inflammation upon allergic reactions. In the latter, neuronal activation was enough to enhance the inflammatory potential of lymphocytes supporting their capacity to produce molecules that promote allergic inflammation.

The research proposed in this project encountered several experimental challenges that were aggravated by the ongoing COVID19 pandemic. While we continued undertaking and troubleshooting the approach proposed in the action, we also investigated the impact of neurons on the immune cells of another essential mucosal tissue: the female reproductive tract (FRT). The FRT is a mucosal site where the immune system must be tightly balanced to protect females from infection but allow pregnancy and tissue healing during the menstrual cycle. However, it is an understudied immune compartment. We discovered that the modulation exerted by subtypes of neurons on the lymphocytes in the FRT is opposite to the effect observed in the lung. Thus, indicating that the particulars of the local regulation of the neuro-immune crosstalk are not necessarily shared across different organs or tissues.

As part of my training and work, we published a review article to integrate and analyze our current knowledge on lymphocytes, asthma, and allergy, including the effect that the nervous system has on them. Moreover, I supervised and mentored several students in my host lab. I could provide my previous expertise in tumour immunology to contribute to the discovery of a new immune axis that promotes colorectal cancer progression.
SIGNAL will continue and expand after the 2-year period of the action finishes. The original plan might have been overly ambitious. However, the support received from the MSCA to undertake this high-risk high-reward project was pivotal to establishing the cornerstone of what will be a broader research program and my scientific career.

The developed tools and knowledge will be implemented to understand the physiology of the neuro-immune crosstalk in allergic lung inflammation. We expect that our work can be published in the next three years making the results available to the scientific community. We expect to generate a transcriptomics dataset of lung immune cells responding to the neuronal cues, which will be valuable to other groups studying neuro-immunology. The models generated here will also help us to develop future projects to study the importance of the nervous system in other immune reactions such as those against tumours. Likewise, we will also explore the role of the neuro-immune crosstalk in other mucosal tissues such as the female reproductive tract and the gut. These offshoot projects will additionally serve to train future students and researchers in the expanding field of neuro-immunology.

The socio-economic impact of SIGNAL is difficult to evaluate since this is a project focused on basic science. The implications that our results might have and how they will translate into the clinical setting are unclear. Stimulation of the vagus nerve and transcranial stimulation, already in the clinic to tackle other diseases, could help to investigate whether modulating the nervous system in humans could be a potential treatment approach for asthma and allergy. Finally, we plan to find ways to bring our discoveries to the public and generate social awareness about the connection between the nervous and immune systems.
Image of the neuro-immune cross-talk in the lung
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