Uric acid as a danger signal in gout and its comorbidities

Abstract

Uric acid is a waste product of purine catabolism. This molecule comes to clinical attention when it nucleates to form crystals of monosodium urate (MSU) in joints or other tissues, and thereby causes the inflammatory disease of gout. Patients with gout frequently suffer from a number of comorbid conditions including hypertension, diabetes mellitus and cardiovascular disease. Why MSU crystals trigger inflammation and are associated with comorbidities of gout has been unclear, but recent studies provide new insights into these issues. Rather than simply being a waste product, uric acid could serve a pathophysiological role as a local alarm signal that alerts the immune system to cell injury and helps to trigger both innate and adaptive immune responses. The inflammatory component of these immune responses is caused when urate crystals trigger both inflammasome-dependent and independent pathways to generate the proinflammatory cytokine IL-1. The resulting bioactive IL-1 stimulates the inflammation of gout and might contribute to the development of other comorbidities. Surprisingly, the same mechanisms underlie the inflammatory response to a number of irritant particles, many of which also cause disease. These new insights help to explain the pathogenesis of gout and point to potential new therapeutic targets for this and other sterile inflammatory diseases.

Figure 1. Biochemistry of uric acid and its homeostasis

Purines are absorbed from the diet through the gut, synthesized in the body and/or derived from the degradation of endogenous DNA and RNA. They are further oxidized by xanthine oxidase. Uric acid is the major end product of purine metabolism in humans. The majority of uric acid is excreted by the kidney and the rest in feces, although a substantial amount of uric acid is reabsorbed at the proximal tubule of the kidney

Figure 2. MHC molecules, antigen presentation and T-cell response

DCs detect and collect antigens and display them as peptides bound to MHC class I and class II molecules. In the presence of DAMPs, and/or PAMPs, DCs can be optimally activated with increased antigen presentation and the expression of costimulatory molecules such as CD80/CD86 (also known as B7.1 and B7.2 antigens to initiate a T-cell immune response. CD4 T cells are stimulated when they recognize peptide-MHC class II complexes plus co-stimulatory molecules and CD8 T cells are stimulated when they recognize peptide MHC class I complexes plus costimulatory molecules. Abbreviations: DAMP, damage-associated molecular pattern; DC, dendritic cell; PAMP, pathogen-associated molecular pattern; TCR, T-cell receptor.

Figure 3. NLRP3 inflammasome activation

The NLRP3 inflammasome is made up of three components: NOD-like receptor protein (including LRRs, NACHT domain and PYD), ASC and pro-caspase-1. Assembly of these components to form inflammasomes leads to the cleavage and activation of caspase-1, which subsequently cleaves pro-IL-1β to form mature IL-1β. Abbreviations: ASC, apoptosis-associated speck-like protein containing a CARD; LRR, leucine-rich repeat region; NLRP3, NACHT, LRR and PYD domains-containing protein 3; PYD. pyrin domain.

Figure 4. ROS and cathepsins involved in NLRP3 inflammasome activation

Internalized irritant particles, including MSU crystals, stimulate phagocytes and mitochondria to produce ROS, which leads to the release of TXNIP from TRX and subsequently to inflammasome activation. Irritant particles also stimulate NLRP3 inflammasomes with activated cathepsins released from membrane-destabilized lysosomes, although this mechanism has not yet been reported for MSU. A dashed line indicates a hypothetical pathway. Activated inflammasomes oligomerize and can form large macroscopic structures that are called specks. Abbreviations: ROS, reactive oxygen species; TRX, thioredoxin; TXNIP, thioredoxin- interacting protein.