Architecture of Peripheral Neuroimmune Circuits and Synapses

Project Information

NeurImmKisses

Grant agreement ID: 101097830

DOI

10.3030/101097830

EC signature date 5 May 2023

Start date 1 January 2024

End date 31 December 2028

Funded under

• European Research Council (ERC)

Total cost

€ 3 500 000,00

EU contribution

€ 3 500 000,00

Coordinated by

FUNDACAO D. ANNA DE SOMMER CHAMPALIMAUD E DR. CARLOS MONTEZ CHAMPALIMAUD
Portugal

Periodic Reporting for period 1 - NeurImmKisses (Architecture of Peripheral Neuroimmune Circuits and Synapses)

Reporting period: 2024-01-01 to 2026-06-30

Summary of the context and overall objectives of the project

Our health requires permanent communication between different systems and organs in our body. In the past decade, we and others have discovered nervous and immune system interactions regulating immunity, tissue repair, body metabolism and behaviour.
Nevertheless, how neuroimmune interactions are organised in space and time, and how their architecture impacts major human conditions remains largely elusive. NeurImmKisses aims at uncovering inter-organ neuroimmune circuit dynamics, architecture and their integration at the core of body physiology and disease.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

DNeurImmKisses has been developing and implementing complementary approaches to interrogate neuroimmune circuits connecting the nervous system to immune cells in different organs of the body. Notably, we have been focusing our work on lung, intestine, pancreas and renal neuroimmune circuit architecture.
We investigated how neuroimmune interactions orchestrate pancreatic endocrine function. We discovered that when blood sugar levels are suboptimal, the adrenergic nervous system instructs intestinal immune cells to migrate to the pancreas, where they trigger the endocrine activity or this organ, thus reestablishing optimal sugar concentrations. These results revealed a neuroimmune inter-organ communication route that promotes pancreatic function and regulation of blood sugar levels.
In parallel we interrogated how intestinal neurons calibrate local immunity to infection. We discovered that intestinal neurons interact with local epithelial cells, forming neuroepithelial units that regulate immune responses against infection. This work identified a multi-tissue axis whereby neuroepithelial interactions distinctively set gut immunity programs (Pirzgaslka et al. Nature Immunol. 2025; Jakob et al. Nature Immunol. 2025).

During the first two years, we mainly focused on building and optimising tools that allow us to track and measure communication between nerves and immune cells directly in living tissues. We implemented viral tracing strategies and created new mouse models in which specific nerve cells can label the immune cells they contact, providing a “history” of recent neuro‑immune interactions. In parallel, we optimised an approach that uses an enzyme and a small tagged peptide to permanently mark immune cells that have recently touched defined groups of neurons or glial cells. We also established a conditional model to switch off a key receptor for the neuropeptide VIP in selected cell types, which will allow us to test how this signal contributes to lung inflammation and repair. Together, these tools now put the project in a strong position to dissect how nerves attract ILC2 into particular lung niches and how this shapes allergy, infection and tissue regeneration.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Our work has already led to several advances that go beyond the initial state of the art. We have shown that nerve‑driven circuits linking the gut and the pancreas help control blood sugar during fasting, revealing a new form of communication between the nervous, immune and endocrine systems. We discovered that nerve‑derived signals acting on intestinal epithelial cells can tilt local immunity towards either type 1 or type 2 responses, thereby influencing susceptibility to different kinds of infections. Finally, we demonstrated that a modified neuropeptide can boost protective immune cells and improve kidney function in a preclinical model of acute kidney injury, providing proof of concept that neuro‑immune pathways can be harnessed therapeutically.