Architecture of Peripheral Neuroimmune Circuits and Synapses

Introduction

Maintenance of health requires the coordination of multiple cellular networks. For example, the immune and nervous systems cooperate to regulate tissue homeostasis. In agreement, our recent work demonstrates that innate lymphoid cells (ILC) integrate neuronal signals to control tissue health and immunity.

Paradigm Shift

These findings are provoking a paradigm shift in our understanding of the immune response, neuroimmune crosstalk, and its potential therapeutic value. Nevertheless, the dynamics of neuroimmune modalities remain elusive, and progress in the field has been hindered by the lack of approaches to explore the identity and plasticity of neuroimmune interactions in vivo.

Hypothesis

Here, we hypothesize that dynamic circuitry codes orchestrate neuro-ILC2 interactions and disease outcomes. To test this hypothesis, we have developed a set of disruptive intercellular labeling neuroimmune toolboxes that we termed KISS and LIPSTIC, which can probe the dynamics of neuro-ILC2 axes in vivo, with cellular specificity and single-cell resolution.

Research Plan

Using these innovative platforms, we plan to:

1. Unravel the architecture of pulmonary neuro-ILC2 circuits.
2. Define cellular identities, outcomes, and plasticity at the neuroimmune interface.
3. Sequentially unravel unappreciated neuro-ILC2 synaptic communication.
4. Define the ultrastructure of these intercellular entities using high-resolution imaging.

Investigation of Neuronal Partners

Finally, by conditionally harnessing the activity of synaptic neuronal partners during airway inflammation and infection, we will investigate their impact on ILC2, their environment, and on disease progression.

Conclusion

Together, these experiments will tackle multiple facets of pioneer, frontier questions, bringing to bear an array of cutting-edge technologies to address and advance, with unprecedented mechanistic and conceptual detail, how the neuroimmune interactome unfolds, in health and disease.