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Enteric-nervous-system-mediated regulation of intestinal inflammation

Project description

Neuro-immune crosstalk contribution to mucosal immune response

Internal and external stimuli are recognised by the nervous and immune systems of the body. Stimuli signal integration and elicitation into proper responses are essential for maintaining homeostasis. However, the mechanisms involved remain unknown. The EU-funded ENTRI project proposes to develop a novel genetic approach and tools for the investigation of the neuro-immune crosstalk at mucosal surfaces, using various disease models. The study will enable selective evaluation of the neuronal and the immune response gene expression and function, resulting in a better understanding of how the neuro-immune crosstalk contributes to parasite immunity or allergic disease development. This project could potentially lead to a general concept of mucosal immune regulation.

Objective

Environmental and internal stimuli are constantly sensed by the body’s two large sensory units, the nervous system and the immune system. Integration of these sensory signals and translation into effector responses are essential for maintaining body homeostasis. While some of the intrinsic pathways of the immune or nervous system have been investigated, how the two sensory interfaces coordinate their responses remains elusive. We have recently investigated neuro-immune interaction at the mucosa of the intestine, which is densely innervated by the enteric nervous system (ENS). Our research has exposed a previously unrecognized pathway used by enteric neurons to shape type 2 immunity at mucosal barriers. Cholinergic enteric neurons produce the neuropeptide Neuromedin U (NMU) to elicit potent activation of type 2 innate lymphoid cells (ILC2s) via Neuromedin U receptor 1, selectively expressed by ILC2s. Interestingly, NMU stimulated protective immunity against the parasite Nippostrongylus brasiliensis but also triggered allergic lung inflammation. Therefore, the NMU-NMUR1 axis provides an excellent opportunity to study how neurons and immune cells interact to regulate immune responses and maintain body homeostasis. We propose to generate and use elegant genetic tools, which will allow us to systematically investigate the consequences of neuro-immune crosstalk at mucosal surfaces in various disease models. These tools will enable us to selectively measure and interfere with neuronal and ILC2 gene expression and function, thereby leading to an unprecedented understanding of how the components of neuro-immune crosstalk contribute to parasite immunity or allergic disease development. Furthermore, we will progress into translational aspects of NMU-regulated immune activation for human immunology. Therefore, our research has the potential to develop basic concepts of mucosal immune regulation and such discoveries could also be harnessed for therapeutic intervention.

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Coordinator

CHARITE - UNIVERSITAETSMEDIZIN BERLIN
Net EU contribution
€ 1 499 638,00
Address
Chariteplatz 1
10117 Berlin
Germany

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Region
Berlin Berlin Berlin
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Beneficiaries (1)