House dust mite drives biphasic immunomodulation of inflammatory dendritic epidermal cells via glucose metabolism in atopic dermatitis

Background The impact of environmental antigens, specifically house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB), on the metabolism of inflammatory dendritic epidermal cells (IDECs) and its role in atopic dermatitis (AD) pathogenesis is poorly understood. This study aimed to characterize IDECs metabolism in AD and study how antigen exposure drives metabolic reprogramming and immune responses. Methods We first analyzed the single-cell RNA transcriptome sequencing data to explore metabolic profiles in IDECs from AD patients. Subsequently, we evaluated the effects of HDM alone or in combination with SEB for 24 h on the energy metabolism, maturation and cytokines secretion of monocytes-derived IDECs (moIDECs) in vitro . Finally, we investigated the dynamic changes of functional and glucose metabolism in moIDECs in vitro treated with HDM at different time points (6 h, 24 h, 48 h, 72 h). Results In AD skin lesions, inflammation- and metabolism-related genes of IDECs are abnormally expressed, and multiple metabolic pathways, including glycolysis/gluconeogenesis, are significantly dysregulated. HDM alone or in combination with SEB activated the glycolysis, induced the upregulation of maturation markers (CD80/83/86) of moIDECs in vitro , and promoted the production of inflammatory cytokines (IL-1β, IL-6, IL-23, IL-10, IL-12 and TNF-α), whereas SEB alone showed no significant effect. Furthermore, we found that HDM dynamically regulated inflammatory immune response of moIDECs. In the early phase (6–24 h), a pro-inflammatory profile predominated, observed with peak levels of IL-6, IFN-γ, IL-18, IL-12, TNF-α and IL-23. This subsequently transitions into the late phase (48–72 h) characterized by an anti-inflammatory shift, marked by elevated IL-10, classical tolerogenic molecules (IDO1, PDL1, and ILT3), and a profile consistent with the potential to induce regulatory T cells (Tregs). Concurrently, metabolic adaptations were observed, with glycolysis peaking at 24 h. Conclusion HDM-driven AD progression is correlated with changes in glucose metabolism and a biphasic immune shift in IDECs. Targeting HDM-responsive metabolic pathways like glycolysis might offer novel therapeutic strategies.