Soluble uric acid suppresses neutrophil-mediated host defense in sepsis

Li, Qiubo; Anders, Juliane; Flora, Kailey; Ehreiser, Louisa; Wendling, Carolin; Zhang, Fengjun; Chang, Liang; Zhao, Danyang; Li, Li; Vogl, Raimund; Soehnlein, Oliver; Steiger, Stefanie (2026): Soluble uric acid suppresses neutrophil-mediated host defense in sepsis. Nature Communications, 17: 4453. ISSN 2041-1723

Abstract

Neutrophils are essential for host defense and inflammation, yet their dysfunction is a hallmark of acquired immunodeficiency in kidney disease, contributing to increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that impaired renal clearance of the metabolite soluble uric acid (sUA) accounts for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9–14 mg/dL) related or unrelated to kidney disease significantly exacerbates the inflammatory immune response in mice with endotoxemia and bacterial sepsis. Despite promoting hyperinflammation, HU simultaneously impairs host defense, an effect that is partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restores neutrophil function. Mechanistically, sUA promotes neutrophil activation and degranulation but impairs phagocytosis, leading to reduced NOX2 expression independent of intracellular MPO levels. This results in diminished ROS production and defective bacterial clearance in human neutrophils. In contrast, sUA has no impact on neutrophil extracellular trap formation following exposure to LPS or E.coli . Together, our findings identify HU as an immunometabolic regulator that amplifies hyperinflammation, while simultaneously impairing effective host defense, suggesting that targeting UA may help to overcome acquired immunodeficiency in kidney disease.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Medizinische Klinik und Poliklinik IV (Endokrinologie, Nephrologie, weitere Sektionen)
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 449437943
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892