The Role of Uric Acid in Inflammasome-Mediated Kidney Injury

Uric Acid and Cell Metabolism

Cellular metabolism profile plays a role in immune cell differentiation and in their operation in physiologic and inflammatory processes.^[67] Cell metabolism involves various enzyme-orchestrated chemical reactions that result in synthesis and degradation of molecules to fuel energy and building blocks for cells. Generally, in a simplistic way, pro-inflammatory cells, such as effector T cells and M1 macrophages, tend to use glycolysis while anti-inflammatory cells, such as M2 macrophages, memory CD8+ T cells and regulatory T cells utilize mitochondrial oxidative phosphorylation and fatty acid oxidation.^[68] Changes in cell metabolism may reflect in cell phenotype and functionality. In some diseases, immune cells with impaired immune function appear to be equally metabolically compromised.^[69]

The effect of sUA on cell metabolism is a still fairly unexplored field in contemporary research. Because metabolic reprogramming plays an important role in macrophage biology, and activated macrophages generate ROS as a microbicide mechanism,^[70] we have proposed in a recent study that the mechanism underlying sUA-induced inflammation is dependent on redox state changes. We observed that sUA promotes mitochondrial modifications and increased mitochondrial ROS production by macrophages, and that such metabolic changes were accompanied by NLRP3 inflammasome activation and IL-1β production.^[13] NLRP3 is a key molecule that connect inflammation and cellular metabolism. NLRP3 inflammasome and caspase-1 activation can directly regulate cellular metabolism by cleaving proteins involved in this process, for example sirtuin-1,^[14] enzymes involved in glycolysis (glyceraldehyde-3-phosphate dehydrogenase, aldolase, enolase, triosephosphate isomerase, and pyruvate kinase),^[15] and nuclear receptor PPARγ.^[16]

In proximal tubular epithelial cells, growing evidence indicates that perturbations in fatty acid and glycolytic metabolism contribute to renal fibrosis by inducing pro-fibrotic mediators, apoptosis, lipotoxicity, and epithelial-to-mesenchymal transition.^[71,72] How sUA modulates the metabolism of renal cells is still unclear. A recent study demonstrated that the liver kinase B1(LKB1)/AMP-activated protein kinase (AMPK)/mTOR pathway was the most abundantly enriched pathway in sUA-stimulated proximal tubular epithelial cells.^[73] Although these data suggest a role for sUA in the metabolism of renal cells, further studies are needed to evaluate in a broader way how sUA-induced metabolic changes – and the associated inflammasome platforms – exert pathogenic or even cytoprotective effects in kidney tissue under injury.

Table 1. Mechanisms and pathways involved in renal NLRP3 inflammasome activation by soluble or crystalline uric acid
Uric acid form	Inflammasome-related mechanisms and signaling	Renal damage
Soluble	Mitochondrial modifications and ROS production by macrophages mTOR upregulation and other changes in proximal tubular epithelial cells metabolism Caspase-1 activation and IL-1β maturation/secretion	Detachment of renal tubular epithelial cells; interstitial mononuclear cell infiltration; oxidative stress; and tubulointerstitial inflammation/fibrosis
Crystalline	Urate crystals phagocytosis by immune cells Activation of renal NF-κB and MAPK pathways Lysosomal damage/rupture and posterior cathepsin B release Caspase-1 activation and IL-1β maturation/secretion Necroptosis and pyroptosis cell-death Damage-associated molecular patterns release by dying cells	Tubule obstruction; oxidative stress; infiltration of immune cells; granuloma formation; and renal inflammation/fibrosis

IL-1β, interleukin-1β; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; NF-κB, nuclear factor kappa B; ROS, reactive oxygen species.