Project Details
Projekt
AHR-mediated mechanisms to overcome vascular barriers in autoimmunity
Applicant
Professor Dr. Sven G. Meuth
Subject Area
Dermatology
Term
since 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 495676076
The development of Multiple sclerosis (MS), one of the most frequent immune-mediated, chronic inflammatory, and neurodegenerative diseases of the central nervous system (CNS), requires a combination of genetic predisposition and environmental triggers. Among these are cigarette smoking, air pollution, low vitamin D levels potentially caused by an insufficient response to ultraviolet (UV) light exposure, dietary intake, the intestinal microbiome, or Epstein-Barr virus infection. Many of these risk factors like UV light, components of cigarette smoke, dietary or microbiome-derived metabolites are sensed by the aryl hydrocarbon receptor (AHR). Sensing frequently takes place in the skin, thereby pointing to a link between the skin and the CNS in MS pathology (skin-CNS axis). Accordingly, in a mouse model of experimental autoimmune encephalomyelitis (EAE) we were able to show that UV irradiation reduced disease severity in wild-type but not in AHR deficient mice. In healthy individuals the blood-brain barrier (BBB), which is established by brain microvascular endothelial cells (BMEC) prevents immune cell migration to the CNS and neuroinflammation. However, in MS the BBB is often described as “leaky” and immune cells are breaching the BBB. Processes involved in controlling BBB integrity are not completely understood and we could show that pharmacological inhibition of AHR in BMEC limited T cell transmigration, which was accompanied by a reduction in ICAM-1 expression. In line with this, mice with an endothelial cell (EC)-specific deletion of AHR developed a less severe EAE compared to wild-type controls, indicating that AHR signaling directly impacts on EC function, BBB integrity, and the infiltration of pathogenic immune cells into the CNS. Hence, in this project we will investigate the role of AHR in the connection of inflammatory processes in the skin and the CNS with a particular focus on its function in skin and brain EC. This will help to better understand pathways mediating the infiltration of immune cells into target tissues as well as the destruction of barrier integrity. In this context we will focus on three different aspects: (1) Investigating the ligand-specific function of AHR in the blood-skin barrier (BSB) and the BBB using skin and brain EC cultures with a particular focus on tight junction proteins, barrier integrity, immune cell penetration, transcriptomic profiling, proteomics and secretomics. (2) Transferring the results obtained in vitro to in vivo settings by using autoimmune mouse models with EC-specific deletion of AHR. (3) Translating the findings from animal models into the human system using vascularized human cortical brain organoids and skin organ cultures. Together, the results from this project will increase our knowledge on how AHR signaling influences immunological barriers. Since EC integrity is implicated in the pathophysiology of autoimmunity, this could potentially result in novel therapeutic options.
DFG Programme
Research Units
