Abstract
The relationship of uric acid with macrophages has not been fully elucidated. We investigated the effect of uric acid on the proinflammatory ability of human macrophages and then examined the possible molecular mechanism involved. Primary human monocytes were differentiated into macrophages for subsequent exposure to 0, 0.23, 0.45, or 0.9 mmol/L uric acid for 12 h, in the presence or absence of 1 mmol/L probenecid. Flow cytometry was used to measure proinflammatory marker production and phagocytic activity that was quantified as a percentage of GFP-labeled Escherichia coli positive macrophages. qPCR was used to measure the macrophage expression of the urate anion transporter 1 (URAT1). As compared to control cells, the production of tumor necrosis factor-alpha (TNF-alpha), toll-like receptor 4 (TLR4), and cluster of differentiation (CD) 11c was significantly increased by uric acid. In contrast, macrophages expressing CD206, CX3C-motif chemokine receptor 1 (CX3CR1), and C-C chemokine receptor type 2 (CCR2) were significantly reduced. Uric acid progressively increased macrophage phagocytic activity and downregulated URAT1 expression. Probenecid—a non-specific blocker of URAT1-dependent uric acid transport—inhibited both proinflammatory cytokine production and phagocytic activity in macrophages that were exposed to uric acid. These results suggest that uric acid has direct proinflammatory effects on macrophages possibly via URAT1.
Highlights
In humans, monosodium urate— referred to as uric acid—is the end-product of purine metabolism [1]
The living monocytes were gated on a forward scatter area/side scatter area plot to assess CD14 positive expression together with TNF-alpha, IL-1 beta, CD11c, CD206, and CX3C-motif chemokine receptor 1 (CX3CR1), and chemokine receptor type 2 (CCR2) (Figure 1D)
We found that uric acid stimulates TNF-alpha production, but not IL-1 beta, in a dose-dependent fashion after confirming that human monocytes were properly differentiated into macrophages using a strategy that combined cell size and complexity as well CD14 expression
Summary
Monosodium urate— referred to as uric acid—is the end-product of purine metabolism [1]. Hyperuricemia is a pathological entity that is characterized by blood uric acid values beyond upper limits that has been largely associated with metabolic syndrome and increased cardiovascular risk [8,9,10]. In this sense, a recent study conducted in 22,983 Chinese adults demonstrated that subjects with hyperuricemia had higher prevalence of cardiovascular risk factors, such as dyslipidemia, hypertension, and type 2 diabetes (T2D), than individuals with normal uric acid values [11]. It is worth mentioning that uric acid concentration associated directly with the number of cardiovascular risk factors; in other words, the cardiovascular risk increases as the uric acid elevates in blood
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