Crystallized but not soluble uric acid elicits pro-inflammatory response in short-term whole blood cultures from healthy men

Abstract

Several epidemiological studies have pointed at serum uric acid (SUA) as an independent risk factor for mortality, diabetes, hypertension, cardiovascular and kidney disease; however, no clear pathogenic pathway is established. Uric acid (UA) crystals show pro-inflammatory properties and can thus create or contribute to the state of chronic low-grade inflammation, a widely accepted pathogenic mechanism in several of the above-mentioned pathologies. On the other hand, soluble uric acid possesses antioxidant properties that might attenuate inflammatory responses. We aimed to explore the net effects of experimentally rising SUA in human whole blood cultures on several mediators of inflammation. Production of TNF-α, IL-1ß, IL-1RA, MCP-1 and IL-8 was assessed upon addition of 200 µM UA, 500 µM UA or monosodium urate (MSU) crystals in the presence or absence of 5 ng/ml lipopolysaccharide (LPS). RT-qPCR and multiplex bead based immunoassay were used to measure mRNA expression and cytokine release at 2 and 4 h of culture, respectively. 14 C labeled UA was used to assess intracellular uptake of UA. We show that crystallized, but not soluble, UA induces production of pro-inflammatory mediators in human whole blood. Soluble UA is internalized in blood cells but does not potentiate or reduce LPS-induced release of cytokines.

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

“…1A) (17,18,20,22,37,38) and solubilizing UA with NaOH (Fig. 1B) (39,44). Checking the prepared solutions for contaminant crystals by light microscopy, we observed microcrystals even after sterile filtration of the UA solutions (5-50 mg/dl) upon prewarming UA but not upon solubilizing UA with NaOH (Fig.…”

Monosodium Urate Crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response

“…Previous studies have shown the inflammatory program triggered by MSUc (18,50,51), and recently a work by Renaudin and colleagues (22) found that MSUc favored glycolytic activity of primed THP-1 cells. However, Renaudin´s work is limiting in identifying the mechanism involved in the MSUc effects in primary mouse and human macrophages.…”

Hyperuricemia in Psoriatic Arthritis: Epidemiology, Pathophysiology, and Clinical Implications

“…Urate in its crystallin shape is phagocytized by monocytes or neutrophils causing the generation of pro-inflammatory cytokines such as IL-1. Furthermore, the internalization of UA crystals by leukocytes leads to production of free radicals, release of cathepsin B and activation of inflammasome (37,38). Interestingly, higher SUA levels have been hypothesized to play a protective role in the development of some neurological disorders such as dementia, multiple sclerosis, Alzheimer's disease and Parkinson's disease (39)(40)(41)(42).…”

“…Urate in its crystallin shape is phagocytized by monocytes or neutrophils causing the generation of pro-inflammatory cytokines such as IL-1. Furthermore, the internalization of UA crystals by leukocytes leads to production of free radicals, release of cathepsin B and activation of inflammasome ( 37 , 38 ).…”