ARYL HYDROCARBON RECEPTOR (AHR) BEYOND ENVIRONMENTAL SENSING: ITS ROLE AS AN INFLAMMATORY REGULATOR IN ASTROCYTE CELLS

Author

Emmanuel Ojo, Southern Illinois University CarbondaleFollow

Date of Award

12-1-2025

Degree Name

Doctor of Philosophy

Department

Pharmacology

First Advisor

Tischkau, Shelley

Abstract

Astrocyte cells are key regulators of both innate and adaptive immune responses that are crucial in regulating neuroinflammation in response to central nervous system insults. These star-shaped cells are involved in the early onset and progression of various neurodegenerative diseases, and in recent years, have become an interesting potential therapeutic target due to their ability to affect outcomes and progression of neuroinflammatory disorders. Aryl hydrocarbon-receptor (AhR), a ligand-activated transcription factor, is expressed in astrocytes. This receptor may contribute to the aging process as it has been linked to several hallmarks of brain aging and neurodegenerative diseases. Evidence highlights the potential relevance of AhR signaling in the pathogenesis of Alzheimer's disease. For example, activation of AhR effectively ameliorates memory deficits in APP/PS1 transgenic mice by increasing Aβ catabolism. Also, elevated levels of AhR in astrocytes of postmortem AD patients’ brains have been reported, which suggests that exploring a role for AhR in mediating astrocyte function may be important. This study explores how AhR affects astrocyte function in response to inflammatory stimuli, with emphasis on Aβ, using in vitro and in vivo acute model systems. To examine the effects of AhR activation on Aβ-induced inflammation in astrocytes, Aβ (1-42) was administered to primary hippocampal astrocyte cultures derived from wild type (WT, C57BL6/J) or AhR germline knockout (AhRKO) mice, pretreated with 6-Formylindolo[3,2-b]carbazole (FICZ), and astrocyte reactivity was accessed. AhR activation attenuates the Aβ-induced, reactive A1 astrocyte phenotype, characterized by decreased astrocyte complement C3 expression and decreased pro-inflammatory cytokine release. In addition, Aβ exposure exacerbated TNF- cytokine release and increased GFAP immunoreactivity in astrocytes derived from AhRKO mice. These findings suggest that AhR activation in astrocytes attenuates development of the neuroinflammatory state, which is known to occur in AD pathology. Using an acute AD animal model in vivo, astrocyte AhR functionality were also examined, since this model closely represents the native conditions of astrocytes in the brain. In response to Aβ injection into the mouse hippocampus in vivo, AhRKO mice demonstrated increased astrocyte soma size which indicates astrocyte hypertrophic states, further reinforcing AhR function in regulating astrocyte responses to neuroinflammation. Thus, our overall findings suggest that AhR activation in astrocytes attenuates development of the neuroinflammatory state, and identifies AhR as an interesting therapeutic target to mitigate neuroinflammation and the progression of AD.