Asymptomatic hyperuricaemia: a silent activator of the innate immune system

Abstract

Asymptomatic hyperuricaemia affects ~20% of the general population in the USA, with variable rates in other countries. Historically, asymptomatic hyperuricaemia was considered a benign laboratory finding with little clinical importance in the absence of gout or kidney stones. Yet, increasing evidence suggests that asymptomatic hyperuricaemia can predict the development of hypertension, obesity, diabetes mellitus and chronic kidney disease and might contribute to disease by stimulating inflammation. Although urate has been classically viewed as an antioxidant with beneficial effects, new data suggest that both crystalline and soluble urate activate various pro-inflammatory pathways. This Review summarizes what is known about the role of urate in the inflammatory response. Further research is needed to define the role of asymptomatic hyperuricaemia in these pro-inflammatory pathways. Asymptomatic hyperuricaemia precedes and potentially contributes to the development of gout and other chronic diseases. This review summarizes what is known about the effects of uric acid on pro-inflammatory responses. Hyperuricaemia is a common laboratory finding that precedes gout and is associated with gout, as well as with hypertension, acute and chronic kidney disease, obesity, metabolic syndrome, fatty liver and diabetes mellitus. The causative role of elevated serum urate in these inflammatory conditions is controversial, but several urate-driven inflammatory mechanisms and other mechanisms have been described. Urate crystals activate the NLRP3 inflammasome and contribute to IL-1β activation through autophagy dysfunction, diminished clearance of damaged organelles, altered redox status and/or AMP-activated protein kinase (AMPK) inhibition. Urate crystals can promote inflammasome-independent mechanisms, such as serine protease-dependent activation of pro-inflammatory cytokines, formation of neutrophil extracellular traps and resolution of inflammation. Soluble urate also has pro-oxidative effects in several cell types and induces inflammatory signalling through several mechanisms, such as MAPK pathway activation, AKT-mTOR activation or AMPK inhibition. Soluble urate and hyperuricaemia exposure could alter the epigenetic programme of innate immune cells and contribute to common adult diseases by promoting persistent inflammatory hyperresponsiveness.