Dexmedetomidine attenuates sepsis-associated NET formation and Th17 polarization through α2-adrenergic receptor-associated regulation of hepatic HPD.

This study investigated whether dexmedetomidine (Dex) attenuates sepsis-induced inflammation and organ injury in association with hepatic 4-hydroxyphenylpyruvate dioxygenase (HPD) regulation through α2-adrenergic receptor (α2-AR) signaling. Using an integrative approach combining in vivo and in vitro models, single-cell RNA sequencing, and 16S rRNA analysis, we found that Dex suppressed NET formation, reduced pro-inflammatory cytokines, and ameliorated liver, kidney, and lung injury in a murine cecal ligation and puncture (CLP) model. Dex decreased hepatic HPD expression, which was accompanied by reduced hepatic HIF-1α levels. Genetic experiments showed that HPD silencing phenocopied several protective effects of Dex, while HPD overexpression weakened Dex's ability to inhibit NETs and provide organ protection. Conditioned-medium experiments indicated that hepatocyte-derived soluble factors convey HPD-associated signals to neutrophils; the inhibitory activity of sh-HPD conditioned medium was heat-sensitive, enriched in the > 3 kDa fraction, and linked to reduced p47phox membrane translocation. Supplementation with 4-hydroxyphenylpyruvate partially restored neutrophil ROS generation, suggesting a role for HPD-related metabolic imbalance. Multi-omics analyses showed that Dex treatment reduced intestinal Th17 cell differentiation, increased Treg proportions, and remodeled gut microbiota composition. These microbiome changes are interpreted as supporting gut-immune remodeling rather than an independent causal factor. In summary, our findings support a hepatocyte-centered immunometabolic model in which Dex treatment is associated with α2-AR-dependent HPD regulation, altered hepatic HIF-1α levels, reduced neutrophil oxidative burst and NET formation, and attenuation of Th17 polarization and organ injury in sepsis.