Immunomodulatory effects of phthiocol: An aryl hydrocarbon receptor ligand regulating conventional dendritic cells and macrophages to alleviate sepsis and lupus severity

Excessive inflammation in sepsis and systemic lupus erythematosus (SLE) is driven by immune dysregulation involving conventional dendritic cells (cDCs), which regulate adaptive immunity, and macrophages, which mediate inflammation and tissue repair. The aryl hydrocarbon receptor (AhR) plays a crucial role in regulating these innate immune cells, suggesting that targeting AhR is a promising strategy to mitigate hyperinflammation in sepsis and SLE. In this study, we demonstrate that phthiocol, a vitamin K analog and AhR ligand, ameliorates hyperinflammation and improves outcomes in both cecal ligation and puncture (CLP)-induced sepsis and Fcgr2b^-/- lupus mouse models. Phthiocol-treated bone-marrow-derived dendritic cells (BM-cDCs) displayed a tolerogenic-like phenotype with increased IL-10 and CD206 expression, and promoted regulatory T cell (Treg) proliferation and IL-10 production, while suppressing IL-17-producing T cell responses. Phthiocol induced M2-like polarization in bone-marrow-derived macrophages (BMMs) with high IL-10 production, in contrast to other AhR ligands, including 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 6-Formylindolo[3,2-b]carbazole (FICZ) that induced M1 polarization. Chromatin immunoprecipitation confirmed AhR binding to the Il10 promoter, revealing direct transcriptional regulation. Furthermore, phthiocol reprogrammed macrophage metabolism by enhancing oxidative phosphorylation and suppressing glycolysis. These immunoregulatory and metabolic effects were abrogated by an AhR antagonist, confirming AhR dependency. Notably, phthiocol exerted similar immunoregulatory effects in activated human monocyte-derived dendritic cells and macrophages, indicating translational potential. Together, these findings position phthiocol as a selective AhR ligand with therapeutic promise for controlling inflammation and restoring immune homeostasis in inflammatory diseases.