The Role of Uric Acid in Inflammasome-Mediated Kidney Injury

Tarcio Teodoro Braga; Orestes Foresto-Neto; Niels Olsen Saraiva Camara


Curr Opin Nephrol Hypertens. 2020;29(4):423-431. 

In This Article

Inflammation and Immune Modulation Triggered by Uric Acid

Hyperuricemia is considered the clinical hallmark of diseases such as acute urate nephropathy and gouty arthropathy. Whether specific initiating mechanisms or a decrease in the negative regulation of the immune system engagement promote the inflammatory cascade or the cell metabolic reprograming in hyperuricemic diseases remains to be revealed. It has been described that high levels of uric acid in the blood cause metabolite content sensing dysregulation, such as mammalian target of rapamycin (mTOR)-related pathways upregulation.[57] However, because of genetic predisposition or way of life, some individuals present higher circulating uric acid levels,[58] a condition that could induce an immunopathology, such as gout. Genetic studies, including genome-wide association studies (GWAS), have identified dozens of susceptibility loci associated with hyperuricemia and gout.[59] These loci mostly influence uric acid levels by affecting pathways such as its renal and gut excretion. Although hyperuricemia might influence oxidative stress and thereby have some effect on inflammatory pathways, it remains to be demonstrated whether polymorphisms and copy numbers of genes associated with hyperuricemia and gout directly modulate inflammatory responses, beyond promoting uric acid crystallization.

In recent years the understanding of additional adverse effects of hyperuricemia has progressed. Early scientific literature suggested an association between uric acid concentration and incidence of cardiovascular diseases, specifically the development of hypertension,[60] metabolic syndrome,[61] endothelial dysfunction,[62] and microalbuminuria.[63] Despite hyperuricemia is able to initiate a proinflammatory pattern even in the absence of crystals formation, as stated above, the majority of studies point out to monosodium urate crystals as the trigger of symptoms of uric acid-related diseases.[59] However, it is also reported that monosodium urate crystals can be present in blood without an inflammatory response, suggesting that regulatory mechanisms may exist to modify the inflammatory response.[59]

Hyperuricemic-related diseases are considered autoinflammatory diseases[64] once they are caused by a disbalance in the innate immune system.[65] The activation of the NLRP3 inflammasome, particularly in neutrophils and macrophages, is of key importance in the pathogenesis of hyperuricemic-related diseases, which leads to the release of pro-inflammatory cytokines such as IL-1β. The crystals are first phagocyted by those cells and promote the assembly and activation of the NLRP3 inflammasome,[10] a cytosolic multiprotein complex that can initiate inflammatory caspases and induce the pyroptosis cell-death pathway.[54,66] Crystal uptake specifically leads to lysosomal damage and rupture and the posterior cathepsin B release, which in turn trigger the NLRP3 inflammasome through its oligomerization.[11]

In addition, neutrophils and macrophages, precipitation of uric acid into monosodium urate crystals is essential for in vitro NLRP3 signaling also in primary human monocytes.[6] It was further demonstrated that uric acid crystals also activate TLR4-NLRP3 inflammasome in PBMCs[7] and in human intestinal cell lines.[8] Moreover, uric acid crystals induce the production of pro-inflammatory mediators in human whole blood cells.[9] Although studies so far in literature have not shown yet the intracellular pathways of uric acid-mediated inflammation in different cell types, there is a consensus that uric acid crystals predict an inflammatory-related response, no matter the cell type. On the other hand, sUA is internalized by whole blood cells but does not alter LPS-induced release of cytokines.[9] A previous study from our group has also demonstrated that, at 200 µM, sUA does not activate human macrophages, however, it displays an inflammatory role in murine cells.[13] Our report suggests that sUA activates the NLRP3 inflammasome and induces IL-1β release.[13] This process is followed by the production of mitochondrial ROS, apoptosis-associated speck-like protein containing a CARD (ASC) formation and caspase-1 activation.[13]