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 also frequently suffer from a number of co-morbid 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 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.

S100A4 and Uric Acid Promote Mesenchymal Stromal Cell Induction of IL-10+/IDO+ Lymphocytes

“…Interestingly, UA itself significantly decreased the proportion of these cells to 1% when MSCs were absent (Fig. 6A), consistent with the immunostimulatory nature of UA (36).…”

The relationships among hyperuricemia, body mass index and impaired renal function in type 2 diabetic patients

“…Hyperuricemia is not only a causative factor for gout [23], but is also a risk factor for CKD [24]. The cytoplasmic NLR Family Pyrin Domain Containing 3 (NLRP3) protein participates in the inflammatory response in both humans and rodents [25].…”

Viruses ‘chew the fat’!?

“…Further, they provide a mechanism for GADD34-mediated suppression of GCSF Receptor signaling, through inhibition of activation of Lyn and STAT3, two important signaling molecules for GCSF Receptor-mediated proliferation and differentiation of myeloid progenitors (Figure 1). 2,3 While GADD34 expression was first identified through a screen for genes expressed following genotoxic injury due to irradiation or alkylating agents, 4 subsequent studies suggest its primary role in the unfolded protein response (UPR). Upregulation of GADD34 occurs during UPR, an evolutionarily conserved pathway to protect cells.…”

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