JOURNAL OF BACTERIOLOGY AND VIROLOGY ISSN:1598-2467(Print) 2093-0429(Online)

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor first identified for its central role in sensing, mediating responses to environmental pollutants, and xenobiotic detoxification. However, recent studies reclassified AhR as a critical regulator of immune responses, barrier integrity, metabolism, and host-microbiota interactions. The receptor has pleiotropic signaling and is involved in canonical and non-canonical pathways in ligand-, tissue-, and context-specific manners that influence transcriptional programs. AhR is broadly distributed in barrier tissues such as the gut, skin, and lung where it controls both mucosal immunity and tissue homeostasis. It plays important roles in several important physiological processes such as epithelial regeneration, cytokine generation, and T cell differentiation. Additionally, AhR senses microbial tryptophan metabolites, which serves as a critical interface between host immunity and the gut microbiota. Its dualistic role as a mediator of both protective and pathological responses emphasizes its complexity in health and disease. Here, we present an overview of the multiple functions of AhR in regulating immunity and maintaining physiological balance, emphasizing its relevance in both health and disease. We further highlight AhR signaling pathways as therapeutic targets for chronic inflammatory, metabolic, and immune-mediated diseases and provide rationale for developing ligand-specific strategies to achieve optimal efficacy and reduced toxicity in clinical applications.