Neuroimmune regulation of lung immunity

PROJECT OVERVIEW

Background

Maintenance of barrier tissue homeostasis and function depends on the integrated activity of multiple cell types. In the lung, disruption of this balance, either spontaneous or in response to infection or inhaled antigens, has severe consequences for human health, manifested as respiratory inflammation and detrimental tissue remodelling such as during viral and bacterial infections, asthma, chronic obstructive pulmonary disease and fibrosis. Whereas the contributions of epithelial, immune and stromal cells to lung inflammatory responses are well understood, only little is known about the role of the nervous system in those conditions. As in other peripheral organs, lung nerves are closely associated with numerous glial cells, however their role in lung immunity is completely unknown.

Preliminary data

Glial cells are crucial for the organisation, function and repair of neural tissues in the central nervous system. Our recent work (Progatzky F, Nature, 2021) and that of others has demonstrated crucial roles for enteric glia in epithelial barrier maintenance, host protection, immunity and tissue repair of the gut, both at steady state and in response to inflammatory challenge. Both enteric and lung glia originate from a common population of neural crest progenitor cells that migrate via the foregut either into the gastrointestinal tract or the lung, suggesting that they exhibit shared functional properties.

Hypothesis

We propose that the intrinsic glia of the lung play important roles in the regulation of pulmonary immunity, both at steady state and during disease. This project aims to understand how lung glia regulate immune homeostasis and inflammation and to determine underlying pathways that control their interaction with other lung tissues in health and disease.

Project plan

This project will employ state-of-the-art single cell RNA sequencing and cutting-edge 3D imaging techniques to define the glial landscape of the lung. To uncover the functional roles of glia in the context of lung inflammation and tissue remodelling, viral vector-mediated lung glia-specific in vivo targeting will be developed and employed in conjunction with mouse models of lung inflammation and analysis of human tissue samples.

Importance

This project is uniquely capable of making fundamental and mechanistic insights into the contributions of glia to the pathogenesis of major respiratory inflammatory diseases that will likely advance the development of therapies and inform our understanding of neuroglial-immune interactions in other barrier tissues.

KEYWORDS (5 WORDS)

Mucosal immunology, neuroimmunology, inflammation, lung

TRAINING OPPORTUNITIES

This interdisciplinary project synergises and integrates experimental approaches, tools and expertise in cellular mucosal immunology and neuroglial biology to uncover fundamental roles of lung glia in immunity. It is therefore suitable for a candidate that has a keen interest in cell biology and neuroimmune interactions and is passionate about discovering basic biological concepts. 

This project will provide high level training in cutting-edge imaging approaches (such as whole tissue visualisation using light sheet microscopy and quantitative and high-resolution confocal microscopy based analysis), mouse in vivo functional genomics and inflammatory models as well as single cell sequencing and data analysis. Pending on project progress, advanced spatial transcriptomic approaches will also be employed. The physiological relevance of mechanistic and functional discoveries to human health and disease will be validated in human tissues samples.

This project is bold, innovative, interdisciplinary and cutting-edge and is suitable for curious and creative candidates that are motivated by challenges and keen to perform experiments that significantly push the boundaries of current knowledge. Our research environment is supportive, friendly and inclusive. We will work with the candidate to develop their research skills and scientific independence and will ensure they get fully integrated in the diverse research environment of the institute. In addition, the candidate will have the opportunity to contribute to the set-up and shape the newly established laboratory and benefit from extensive training and close interactions with the principal investigator.

Interested candidates are strongly encouraged to contact Dr Fränze Progatzky by email.

KEY PUBLICATIONS (5 MAXIMUM)

Progatzky, F., et al., Regulation of intestinal immunity and tissue repair by enteric glia. Nature, 2021. DOI:10.1038/s41586-021-04006-z

Progatzky, F. and V. Pachnis, The role of enteric glia in intestinal immunity. Curr Opin Immunol, 2022. DOI:10.1016/j.coi.2022.102183

Laddach A*, […] Progatzky F, et al, “A branching model of lineage differentiation underpinning the neurogenic potential of enteric glia”. bioRxiv, 2023 (https://www.biorxiv.org/content/10.1101/2022.07.12.499640v1), manuscript accepted for publication in Nature Communication)

THEMES (4 KEY THEMES)

Biological sciences, pulmonary inflammation, glial biology, cellular immunology

CONTACT INFORMATION OF ALL SUPERVISORS

Email franze.progatzky@kennedy.ox.ac.uk

Email tal.arnon@kennedy.ox.ac.uk