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Soluble uric acid inhibits ß2 integrin-mediated neutrophil recruitment in innate immunity.
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.
  • Ma Q; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Immler R; Walter-Brendel-Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Pruenster M; Walter-Brendel-Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Sellmayr M; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Li C; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • von Brunn A; Max von Pettenkofer-Institute, Ludwig-Maximilians-University (LMU) Munich and German Center for Infection Research (DZIF), Munich, Germany.
  • von Brunn B; Max von Pettenkofer-Institute, Ludwig-Maximilians-University (LMU) Munich and German Center for Infection Research (DZIF), Munich, Germany.
  • Ehmann R; Bundeswehr Institute of Microbiology, Munich, Germany.
  • Wölfel R; Bundeswehr Institute of Microbiology, Munich, Germany.
  • Napoli M; Walter-Brendel-Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Li Q; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Romagnani P; Department of Biomedical Experimental and Clinical Sciences "Maria Serio," University of Florence, Florence, Italy; and.
  • Böttcher RT; Department of Molecular Medicine, Max Planck Institute for Biochemistry, Martinsried, Germany.
  • Sperandio M; Walter-Brendel-Center of Experimental Medicine, Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Anders HJ; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
  • Steiger S; Division of Nephrology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany.
Blood ; 139(23): 3402-3417, 2022 06 09.
Article in English | MEDLINE | ID: covidwho-1862095
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 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 ß2 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.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Uric Acid / CD18 Antigens Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Blood Year: 2022 Document Type: Article Affiliation country: Blood.2021011234

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Uric Acid / CD18 Antigens Type of study: Prognostic study Limits: Animals / Humans Language: English Journal: Blood Year: 2022 Document Type: Article Affiliation country: Blood.2021011234