Soluble uric acid inhibits β2 integrin–mediated neutrophil recruitment in innate immunity

• Published in: Blood Vol. 139; no. 23; pp. 3402 - 3417
• Main Authors: Ma, Qiuyue, Immler, Roland, Pruenster, Monika, Sellmayr, Markus, Li, Chenyu, von Brunn, Albrecht, von Brunn, Brigitte, Ehmann, Rosina, Wölfel, Roman, Napoli, Matteo, Li, Qiubo, Romagnani, Paola, Böttcher, Ralph Thomas, Sperandio, Markus, Anders, Hans-Joachim, Steiger, Stefanie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.06.2022; The American Society of Hematology
• Subjects: Animals; CD18 Antigens - metabolism; Humans; Immunity, Innate; Immunobiology and Immunotherapy; Inflammation; Mice; Neutrophil Infiltration; Neutrophils; Uric Acid - pharmacology; Uric Acid - urine
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood.2021011234

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 coronavirus-related 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 β2 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. •Hyperuricemia suppresses neutrophil adhesion and extravasation during sterile inflammation.•Uric acid impairs neutrophil migration by suppressing β2 integrin activity/recycling and cytoskeletal dynamics upon urate transporter–mediated uric acid uptake. [Display omitted]