Neuron/mast cell interactions in skin diseases

Informations projet

NEMESIS

N° de convention de subvention: 749629

DOI

10.3030/749629

Projet clôturé le 31 Decembre 2018

Date de signature de la CE 16 Juin 2017

Date de début 1 Juillet 2017

Date de fin 30 Juin 2019

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 185 076,00

Contribution de l’UE

€ 185 076,00

Coordonné par

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - NEMESIS (Neuron/mast cell interactions in skin diseases)

Période du rapport: 2017-07-01 au 2019-06-30

Résumé du contexte et des objectifs généraux du projet

The atopic dermatitis.
Atopic dermatitis (AD) also known as eczema is a chronic itch inflammatory skin disease that affects one in ten people. Moderate-to severe AD may have a strong impact on health-related quality of life, especially due to itch burden. AD is frequently associated with atopic comorbidities such as asthma and allergic rhinitis. The etiology of AD is incompletely understood, but many factors (i.e. complex interactions between environmental and genetic factors, involvement of various types of immune or structural cells and multiple signaling pathways) are thought to contribute to the development of skin lesions in AD. There are accumulating evidences showing that cutaneous sensory neurons play a critical role in such diseases. This project aims to investigate a potential new therapeutic target in the prevention and treatment of allergic skin inflammation: the interactions between specific nociceptors (nerves that sense damaging stimuli by sending signals to the spinal cord and brain) and type 2 immunity.

Objectives.
Aim 1. Elucidate the role of nociceptors in the development of AD-like pathology.
Aim 2. Identify the role of nociceptor/immune cell cross-talk in the development of AD-like pathology.
Aim 3. Test the impact of nociceptor/immune cell cross-talk on skin barrier function.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

We have succeed in the validation of one of the key hypothesis proposed in the project NEMESIS. Using different animal models, we identified sensory neurons as a key cell type involved in the development of skin lesions in a mouse model that shares many similarities with the human pathology. We are now currently investigating whether those neurons have the potential to influence type 2 immune response and if so, by which mechanisms. We also have developed a new imaging system enabling us to analyze simultaneously the activation of sensory neurons and immune cells in living mice. We hope this method will enable us to better understand how neurons and immune cells communicate and potentially regulate the development of AD pathology.

This Marie Curie Fellowship has paved the way toward the development of a substantially larger and very ambitious ERC-funded project with the ambition of developing a new therapeutic approach for the treatment and prevention of AD pathology based on those observations. Results obtained in this context will be the object of international patents and publications in peer-reviewed medical journals.

Scientific publications associated with the Marie Curie Fellowship but not directly linked to the NEMESIS project:

Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity.
Gaudenzio N, Marichal T, Galli SJ, Reber LL. Front Immunol. 2018 Jun 5;9:1275. doi: 10.3389/fimmu.2018.01275. eCollection 2018. Review.

The tyrosine kinase inhibitor imatinib mesylate suppresses uric acid crystal-induced acute gouty arthritis in mice.
Reber LL, Starkl P, Balbino B, Sibilano R, Gaudenzio N, Rogalla S, Sensarn S, Kang D, Raghu H, Sokolove J, Robinson WH, Contag CH, Tsai M, Galli SJ.
PLoS One. 2017 Oct 5;12(10):e0185704. doi: 10.1371/journal.pone.0185704. eCollection 2017.

Early termination of the project:
The NEMESIS project has been the object of an early termination due to the obtention of an ERC Starting Grant, which is based on the data generated in the NEMESIS project.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

The NEMESIS project can have major scientific and socio-economic implications.

AD is a major chronic skin disease of high impact on patient quality of life characterized the presence of intense itching sensations, hypersensitivity to innocuous substances and painful inflammatory skin lesions heavily colonized by exotoxin-producing Staphylococcus aureus. This project aims to explore the multifaceted aspect of AD pathology, by analyzing the role of interactions between primary sensory neurons (regulating itching sensation in patients), immune system and skin barrier proteins (both suspected to contribute to disease development) in regulating AD-like features. By using such experimental design, we aim to build a synergy between neurobiology, immunology and clinical dermatology and contribute to pave the way toward better understanding of this complex disease.

The “neural regulation of immune response” is an emerging and rapidly evolving field that is based on a cross-disciplinary approach to better understand the etiology of complex human diseases. It is our intention to efficiently contribute to our understanding of the sophisticated neuro-immune interactions in the context of inflammation. In the work performed in the project NEMESIS, we combine unique in vivo models and new 3-D imaging methods to better understand the role of interactions between defined subtypes of nociceptors and immune cells in the development of type 2 immunity, disruption of skin barrier architecture, and development of AD-like pathology.

This work thus will address significant gaps in our knowledge about the complex pathophysiology of AD and has the potential to identify such neuro-immune interactions as a promising new therapeutic target in AD, and perhaps other disorders in which immune cells and sensory neurons are suspected to play an important role.

Summary of the working hypothesis