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Kidney Week

Abstract: PO0636

Soluble Uric Acid, a Negative Regulator of Monocyte Activation in Innate Immunity

Session Information

  • CKD Mechanisms - 2
    October 22, 2020 | Location: On-Demand
    Abstract Time: 10:00 AM - 12:00 PM

Category: CKD (Non-Dialysis)

  • 2103 CKD (Non-Dialysis): Mechanisms

Authors

  • Steiger, Stefanie, Division of Nephrology, Department of Medicine IV, LMU Hospital, Munchen, Bayern, Germany
  • Ma, Qiuyue, Division of Nephrology, Department of Medicine IV, LMU Hospital, Munchen, Bayern, Germany
  • Lindenmeyer, Maja, Department of Medicine III, University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany
  • Romagnani, Paola, Department of Biomedical Experimental and Clinical Sciences Maria Serio, Univerisity of Florence, Florence, Italy
  • Anders, Hans J., Division of Nephrology, Department of Medicine IV, LMU Hospital, Munchen, Bayern, Germany
Background

While monosodium urate (MSU) crystals are known to trigger acute inflammation in gouty arthritis, 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 a novel animal model with clinically relevant levels of asymptomatic hyperuricemia (HU) and gouty arthritis can ultimately clarify this issue.

Methods

Soluble UA was prepared either by pre-warming or solubilized with NaOH. THP-1 cells or CD14+ monocytes from patients with HU and healthy individuals were pre-incubated with sUA prior to stimulation with MSU crystals or LPS. Intracellular sUA uptake via urate transporters was quantified using siRNA technology. In vivo, Alb-creERT2;Glut9lox/lox and Glut9lox/lox control mice were injected with tamoxifen and placed on a chow diet with inosine to induce HU. After 3 weeks, MSU crystals or vehicle were injected into air pouches, and leukocyte infiltration and the extent of inflammation were assessed by flow cytometry, RT-PCR, ELISA.

Results

We found that pre-warmed UA created erroneous results because of microcrystal contaminants triggering IL-1β release. Solubilizing UA with NaOH avoided such artifact. This microcrystal-free preparation suppressed LPS- or MSU crystal-induced monocyte activation, a process dependent on the intracellular uptake of sUA via the urate transporter SLC2A9/GLUT9. CD14+ monocytes isolated from HU patients were less responsive to inflammatory stimuli compared to monocytes from healthy individuals. Treatment with plasma from HU patients impaired the inflammatory function of CD14+ monocytes, an effect fully reversible by removing sUA from HU plasma with rasburicase. Moreover, Alb-creERT2;Glut9lox/lox mice with HU (serum UA of 9-11mg/dL) showed a suppressed inflammatory response to MSU crystals compared to Glut9lox/lox controls without HU.

Conclusion

We unravel a technical explanation for discrepancies in the published literature on immune effects of sUA and identify HU as an intrinsic suppressor of innate immunity, where 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 inhibitor of sterile inflammation and may explain several clinical observations in the context of gout and CKD.

Funding

  • Government Support - Non-U.S.