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

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-1β 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;Glut9lox/lox mice with hyperuricemia (serum UA of 9–11 mg/dl) showed a suppressed inflammatory response to MSU crystals compared with Glut9lox/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.

Serum uric acid, disease severity and outcomes in COVID-19

“…First, studies have shown uric acid to be an important antioxidant [ 25 ] and poor outcomes in patients with hypouricemia might be related to reduced defense against oxidative stress. Second, uric acid was found to act as an endogenous modulator of innate immunity, and it is tempting to speculate that low levels of serum uric acid may therefore exacerbate the cytokine storm observed during COVID-19 [ 26 , 27 ]. Third, recent evidence demonstrated that acute and severe hypouricemia induced in healthy individuals causes endothelial dysfunction, reduces blood pressure, decreases myeloperoxidase activity and increases lipid peroxidation [ 28 ].…”

Why Does Hyperuricemia Not Necessarily Induce Gout?

“…The major symptom of a gout flare is the MSU crystal-induced sterile inflammation with UA controversially being an intrinsic inhibitor of MSU crystal-induced tissue inflammation [49] and a direct promoter in inflammation in vivo [50]. Hyperuricemia could induce an activated status of inflammation [51] or autoinflammation [52].…”

“…Moreover, asymptomatic hyperuricemia patients usually display less potency of inflammation with a lower number of NKG2D + (activating receptors of simulation of cytotoxicity) NK cells [63]. It could be speculated that under hyperuricemia condition the UA paradox interrelationship of the contradictory dual effects of inflammation [49,50] results from SUA "neutralizing" the inflammation produced oxygen species to protect tissue damages. It has also been discovered that some lipids from diet or alcohol consumption could directly trigger gout flares by activation of NALP-3 inflammasome through binding to toll-like receptors [64] or alteration of glucose and apolipoprotein metabolism [65], respectively.…”

Why Hyperuricemia Does Not Necessarily Induce Gout?

“…The major symptom of a gout attack or flare is the MSU crystal-induced sterile inflammation with UA controversially being an intrinsic inhibitor of MSU crystal-induced tissue inflammation [49] and a direct promoter in inflammation in vivo [50]. Hyperuricemia could induce an activated status of inflammation [51] or autoinflammation [52].…”

“…Moreover, asymptomatic hyperuricemia patients usually display less potency of inflammation with a lower number of NKG2D + (activating receptors of simulation of cytotoxicity) NK cells [63]. It could be speculated that under hyperuricemia condition the UA paradox inter-relationship of the contradictory dual-effects to inflammation [49,50] is resulted from SUA to "neutralize" the inflammation produced oxygen species to protect tissue damages. It has also been discovered that some lipids from diet or alcohol consumption could directly trigger gout flare by activation of NALP-3 inflammasome through binding to toll-like receptors [64] or alteration of glucose and apolipoprotein metabolism [65], respectively.…”