GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE294nnn/GSE294890/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294890GEOGSEfalseSoluble uric acid suppresses neutrophil-mediated host defense in sepsisNeutrophils play a critical role in host defense and sterile inflammation. However, neutrophil dysfunction is a hallmark of the acquired immunodeficiency in kidney disease, contributing to an increased susceptibility to infections such as peritonitis, sepsis, and pneumonia. We speculated that the impaired renal clearance of the metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-14 mg/dL) related or unrelated to kidney disease significantly exacerbated the inflammatory immune response to infection by impairing neutrophil dynamics and functions in mice with mono- and polybacterial sepsis. This aggravated inflammatory response was partially reversible by lowering UA levels with febuxostat. We validated these findings in vitro using either neutrophils or serum from healthy individuals or hyperuricemic patients with chronic kidney disease. Depleting UA partially restored neutrophil dysfunction. Mechanistically, sUA impaired the phagocytic capability, bacterial clearance, and oxidative burst in neutrophils by modulating cytoskeletal dynamics and promoting degranulation, processes essential for host defense. In contrast, sUA had no impact on neutrophil extracellular trap formation in neutrophils from healthy subjects exposed to LPS or E.coli. Our findings identify HU related or unrelated to kidney disease as immune regulator in exacerbating the inflammatory response during sepsis, primarily by impairing neutrophil-mediated phagocytosis, pathogen clearance, and oxidative burst. Targeting UA may help to overcome the acquired immunodeficiency during infection, while aggravating sterile forms of inflammation.2026/04/14GSE294890GSM9226149GSM9226141GSM9226142GSM9226143GSM9226144GSM9226145GSM8927770GSM9226146GSM9226147GSM8927771GSM8927772GSM9226148GSM9226140GSM9226138GSM9226139GSM8927763GSM9226131GSM9226132GSM8927764GSM8927765GSM9226133GSM9226134GSM9226135GSM9226136GSM9226137GSM8927766GSM8927767GSM9226150GSM8927768GSM892776928337294890Homo sapiens