The role of IL-17 signaling in the enteric nervous system for immune regulation, gut physiology and central nervous system sensation of intestinal IL-17 inflammation

• Applicant: Dr. Mario Witkowski
• Subject Area: Immunology ; Medical Microbiology and Mycology, Hygiene, Molecular Infection Biology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 532555998

Mucosal immune responses and their resulting effector cytokines are essential for pathogen clearance and tissue homeostasis. However, if dysregulated, cytokine responses can also trigger intestinal inflammation which is associated with altered gut physiological functions and in some patients with neuropsychiatric symptoms. Despite the importance, the molecular networks which regulate the immune homeostatic programs in the gut are not fully understood. The enteric nervous system (ENS) has recently been assigned a critical role for immune regulation and tissue homeostasis. Intriguingly, our preliminary data show that ENS neurons are equipped with the machinery to sense inflammatory cytokine signals. We hypothesize that specialized ENS neurons function as inflammatory sensors to regulate the intestinal immune response along with gut physiological functions in the context of inflammation. We further hypothesize that cytokine-sensitive ENS neurons are involved in the sensation of intestinal inflammation in the central nervous system (CNS). In this project, we test these hypotheses for IL-17 inflammation as a model system. First, we combine IL-17 receptor (IL-17R) mouse reporter lines which have been developed in the host laboratory with a mouse model for intestinal IL-17 inflammation to characterize the anatomical niche where IL-17-producing immune cells and responsive ENS neurons interact. Next, we implement state-of-the-art techniques for neuronal manipulation such as chemogenetics and optogenetics to study the functional role of IL-17 signaling in the ENS. To this end, peristalsis and intestinal transit will be analyzed after chemogenetic silencing of IL-17R+ ENS neurons. Further, immune regulation by cytokine-sensitive neurons will be analyzed based on expression of neuropeptides and neuro-immune modulators. Particularly, we test whether ENS neurons can integrate inflammatory signals to adjust intestinal immune responses and whether this axis limits intestinal inflammation and the associated tissue damage. Finally, to test whether IL-17R-expressing ENS neurons are involved in the CNS sensation of intestinal IL-17 inflammation, we will map the responding brain regions during IL-17-driven colitis via a Fos-dependent genetic recombination system (Fos-TRAP mice). The specific role of IL-17R-sensitive ENS neurons for this process will be investigated by mapping the CNS response in gain and loss of function models for IL-17R+ ENS neurons and by contrasting the results. Taken together, this project will test the role of the ENS as inflammatory sensor and its significance for immune regulation, peristalsis and the CNS response to intestinal inflammation. The results may help to identify novel (neuronal) targets for therapeutic approaches to modulate inflammatory immune responses and to attenuate neuropsychiatric symptoms observed in the context of chronic intestinal inflammation.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Gloria Choi, Ph.D.