Aryl hydrocarbon receptor pathway mediates cigarette smoke-induced skin inflammation and sebaceous gland hyperplasia

Cigarette smoke (CS) represents a major exogenous stimulus associated with various skin pathologies, yet the precise mechanisms driving skin inflammation and glandular dysfunction remain incompletely elucidated. The aryl hydrocarbon receptor (AhR) is a transcription factor involved in various cellular functions, though its role in skin is unclear. This study investigates how cigarette smoke extract (CSE) mediates skin inflammation and abnormal glandular hyperplasia via AhR activation. In a CS-exposed mouse model, histopathological staining revealed that CS exposure induced inflammatory cell infiltration, mast cell degranulation and increased sebaceous gland cells. Immunohistochemistry showed higher levels of CD68, lymphocyte antigen 6 family member G (Ly-6G), and AhR, along with increased mRNA expression of inflammatory cytokines such as interleukin-1β (IL-1β) and interleukin-6 (IL-6). Integrated network toxicology and transcriptomics suggested that nicotine derivatives, indoles, and bipyridyl components in CSE activate the AhR complex, increasing cytochromes P450 family 1 (CYP1) subfamily A member 1 (CYP1A1), CYP1B1, and glutathione S-transferase (GST), while promoting the release of inflammatory mediators. Co-culture experiments with 3T3-L1 preadipocytes and RAW264.7 macrophages indicated that CSE-treated macrophages enhance adipocyte proliferation and lipid accumulation via paracrine signaling. In summary, CS exposure activates the AhR pathway, leading to increased inflammation and sebaceous gland cell proliferation, which collectively contribute to inflammatory infiltration, sebaceous gland hyperplasia, and collagen remodeling in skin tissue. These findings offer deeper theoretical insights for preventing and treating CS-related skin diseases.