The nervous system and the immune system, as the body’s primary sensory interfaces, play a crucial role in maintaining body homeostasis. The preservation of homeostasis at mucosal barriers, particularly the intestinal mucosa, is vital for preventing inflammation. The impact of chronic intestinal inflammation, as seen in conditions like inflammatory bowel disease (IBD), is not just a health concern but also has significant socioeconomic implications.
Inflammation in the intestine is triggered and maintained by the mucosal immune system, which comprises tissue-resident immune cells, including innate lymphoid cells (ILCs), which are enriched at mucosal barriers and maintain barrier homeostasis. For this purpose, immune cells interact with the surrounding cell type, including but not limited to neurons, in the tissue niche.
Enteric-associated neurons can be subdivided into the intrinsic innervation and extrinsic innervation of the intestine. The intrinsic innervation is embedded in the gut wall and called the enteric nervous system (ENS), whereas the extrinsic fibers originate from ganglia outside of the intestine. The interplay between ENS and the immune system influences chronic inflammation, for example, in IBD, and hallmarks of this disease, such as pain, cramping, and diarrhea, could be explained by ENS functions. We could recently show that the ENS is altered in the context of IBD. In fact, there several findings suggest a close interaction between the nervous system and the immune system. However, how these two systems exchange information and coordinate responses with consequences for chronic intestinal inflammatory disorders is poorly understood, and elucidating this is the underlying topic of this proposal.
To this end, we characterized the changes occurring in the ENS during intestinal inflammation because neurons could participate in inflammation, for example, via the expression of cytokine receptors. Therefore, we focused on how enteric neurons sense and react to intestinal inflammation and what the functional consequences are. Based on our data, we propose the following conclusions. The ENS is dynamically regulated by and senses inflammation. Enteric neurons adjust their metabolism and production of inflammatory mediators accordingly and undergo iron-mediated cell death. The cell death in enteric neurons is regulated by interferon signals sensed by neurons via Ifnar1.
From the side of the immune system, we investigated group 2 innate lymphoid cells (ILC2s) as a component of the mucosal immune system and how they are regulated by the factors derived from various cell types in the tissue niche, such as neurons, stromal cells and epithelial cells. The cells in the tissue niche form functional units promoting neuro-immune interactions and type 2 immune responses. Therefore, we hypothesize that neuro-ILC units have an important role in the regulation of inflammation, immunity, and allergy at mucosal barriers.
Indeed, our data demonstrate that ILC2s have essential functions in the regulation of mucosal inflammation relevant to allergic asthma and anti-worm immunity and control the homeostasis of immune cells, such as eosinophils and B1 related to allergy.
Overall, our study exposes the ENS and the interfaces with the type 2 immune responses as an essential signaling hub for intestinal homeostasis with important consequences for mucosal immunity and human health.
