Soluble Uric Acid Is an Intrinsic Negative Regulator of Monocyte Activation in Monosodium Urate Crystal-Induced Tissue Inflammation

Ma, Qiuyue; Honarpisheh, Mohsen; Li, Chenyu; Sellmayr, Markus; Lindenmeyer, Maja; Boehland, Claudia; Romagnani, Paola; Anders, Hans-Joachim und Steiger, Stefanie (2020): Soluble Uric Acid Is an Intrinsic Negative Regulator of Monocyte Activation in Monosodium Urate Crystal-Induced Tissue Inflammation. In: Journal of Immunology, Bd. 205, Nr. 3: S. 789-800

Abstract

Although monosodium urate (MSU) crystals are known to trigger inflammation, published data on soluble uric acid (sUA) in this context are discrepant. We hypothesized that diverse sUA preparation methods account for this discrepancy and that an animal model with clinically relevant levels of asymptomatic hyperuricemia and gouty arthritis can ultimately clarify this issue. To test this, we cultured human monocytes with different sUA preparation solutions and found that solubilizing uric acid (UA) by prewarming created erroneous results because of UA microcrystal contaminants triggering IL-1 beta release. Solubilizing UA with NaOH avoided this artifact, and this microcrystal-free preparation suppressed LPS- or MSU crystal-induced monocyte activation, a process depending on the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. CD14(+) monocytes isolated from hyperuricemic patients were less responsive to inflammatory stimuli compared with monocytes from healthy individuals. Treatment with plasma from hyperuricemic patients impaired the inflammatory function of CD14(+) monocytes, an effect fully reversible by removing sUA from hyperuricemic plasma. Moreover, Alb-creERT2;Glut9(lox/lox) mice with hyperuricemia (serum UA of 9-11 mg/di) showed a suppressed inflammatory response to MSU crystals compared with Glut9(lox/lox) controls without hyperuricemia. Taken together, we unravel a technical explanation for discrepancies in the published literature on immune effects of sUA and identify hyperuricemia as an intrinsic suppressor of innate immunity, in which sUA modulates the capacity of monocytes to respond to danger signals. Thus, sUA is not only a substrate for the formation of MSU crystals but also an intrinsic inhibitor of MSU crystal-induced tissue inflammation.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0022-1767
• Sprache: Englisch