Soluble uric acid inhibits beta(2) integrin-mediated neutrophil recruitment in innate immunity

Ma, Qiuyue; Immler, Roland; Pruenster, Monika; Sellmayr, Markus; Li, Chenyu; Brunn, Albrecht von; Brunn, Brigitte von; Ehmann, Rosina; Woelfel, Roman; Napoli, Matteo; Li, Qiubo; Romagnani, Paola; Boettcher, Ralph Thomas; Sperandio, Markus; Anders, Hans-Joachim und Steiger, Stefanie (2022): Soluble uric acid inhibits beta(2) integrin-mediated neutrophil recruitment in innate immunity. In: Blood, Bd. 139, Nr. 23: S. 3402-3417

Abstract

Neutrophils are key players during host defense and sterile inflammation. Neutrophil dysfunction is a characteristic feature of the acquired immunodeficiency during kidney disease. We speculated that the impaired renal clearance of the intrinsic purine metabolite soluble uric acid (sUA) may account for neutrophil dysfunction. Indeed, hyperuricemia (HU, serum UA of 9-12 mg/dL) related or unrelated to kidney dysfunction significantly diminished neutrophil adhesion and extravasation in mice with crystal- and coronavirusrelated sterile inflammation using intravital microscopy and an air pouch model. This impaired neutrophil recruitment was partially reversible by depleting UA with rasburicase. We validated these findings in vitro using either neutrophils or serum from patients with kidney dysfunction-related HU with or without UA depletion, which partially normalized the defective migration of neutrophils. Mechanistically, sUA impaired beta(2) integrin activity and internalization/recycling by regulating intracellular pH and cytoskeletal dynamics, physiological processes that are known to alter the migratory and phagocytic capability of neutrophils. This effect was fully reversible by blocking intracellular uptake of sUA via urate transporters. In contrast, sUA had no effect on neutrophil extracellular trap formation in neutrophils from healthy subjects or patients with kidney dysfunction. Our results identify an unexpected immunoregulatory role of the intrinsic purine metabolite sUA, which contrasts the well-known immunostimulatory effects of crystalline UA. Specifically targeting UA may help to overcome certain forms of immunodeficiency, for example in kidney dysfunction, but may enhance sterile forms of inflammation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch