Role of enteric glia in acute and chronic inflammation

• Applicant: Professor Dr. Sven Wehner
• Subject Area: General and Visceral Surgery
• Term: from 2015 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 282119756

Enteric glial cells (EGC) are distributed along the complete intestine and are localized in all positions relevant to maintain enteral homeostasis. EGC stay in close proximity to resident macrophages, epithelial cells and nerves. Meanwhile we know that EGC crucially participate in intestinal inflammation as shown within EGC-ablated transgenic mice that suffer from a severe jejuno-ileitis. This points toward an immunoregulatory function of EGC.IIn a model of postoperative ileus (POI), an acute intestinal inflammation and dysmotility, we recently demonstrated that mice deficient for MyD88 or IL-1 receptor type 1(IL1R1), were protected from POI. We found that IL1R1 was expressed by human and mouse EGC and cultured EGC released Interleukin-6 and MCP-1 in response to IL-1 stimulation. EGC activation during POI was confirmed by increased expression of three prototypical activation markers, GFAP, Nestin and S100B. Furthermore, we demonstrated an EGC activation in a mouse model of chemically induced (DSS) chronic colitis. These data point toward a proinflammatory function of EGC and undoubtedly demonstrate involvement of EGC in intestinal inflammation. However, their significance and detailed function in intestinal disease states is unknown. In this project we focus on three major question:(1) The significance of an EGC specific IL-1 signalling will be analysed within conditional knockout mice (GFAPcre+/-/Myd88fl/fl), deficient for MyD88 and IL-1R1 signalling within EGC. In a POI model, gene expression and flow cytometry as well as contractility and motility measurements will be performed in a postoperative time course. In a DSS-colitis model in these mice we will focus on intestinal barrier function of mucosa probes from these mice. We will measure nitric oxide intermediates and other proteins involved in barrier homeostasis. Additionally, barrier integrity will be determined by Ussing chamber experiments in a collaborative work. (2) Neurotransmitters are known to modulate intestinal inflammation. Herein we focus on purinergic, cholinergic but also sympathetic/adrenergic effects on EGC function during IL-1-triggered inflammation. In vitro cultures of EGC under selective neurotransmitter receptor (ant)agonism and IL-1 stimulation and selective surgical denervation studies in the murine disease models will be performed (3) Finally, we will investigate the interaction of EGC and resident macrophages. The latter play a key role in the trigger phase of intestinal inflammation, particularly in POI. In cocultures of both cell types, release of the EGC-specific S100B immune activator and its effects on macrophages will be analysed. In vivo experiments in GFAPcre+/-/Myd88fl/fl will help to evaluate the significance of this pathway in POI. Subsumed we expect new insights about the immunological function of EGC that could be helpful in the treatment or prevention of acute or chronic inflammatory intestinal diseases.

• DFG Programme: Research Grants