Caught red-handed: uric acid is an agent of inflammation

Shi, Yan

doi:10.1172/jci43132

Cited by 67 publications

(58 citation statements)

References 22 publications

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“…It was recently demonstrated that OA cartilage is associated with a reduction and loss of regulators of the autophagy pathway (ULK, Beclin-1, and LC3 expression) and an increase in cell death (characterized by increased expression of PARP p85) (14). The extent to which uric acid is released during autophagy is currently unknown, but cell death could result in local supersaturation of uric acid as cytolysis generates large quantities of purines from RNA and DNA (17). As suggested by Matzinger's theories, the release of uric acid could provide an inflammatory danger signal responsible for activating a chronic immune inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Denoble¹,

Huffman²,

Stäbler³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

236

178

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Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acidactivated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.arthritis | inflammation | interleukin-18 | interleukin-1β | tumor necrosis factor alpha U ric acid (UA) is constitutively present in normal cells, increased in concentration when cells are injured, and released from dying cells (1). On the basis of a theory proposed by Matzinger, the products of cell stress and tissue damage may represent "danger signals" that function as endogenous adjuvants recognized by the immune system (2). Matzinger proposed that immunity is controlled by an internal conversation between tissues and the cells of the immune system (3). This proposal introduced a new immunological model of an immune system capable of sensing cellular stress and tissue damage (4). Shi subsequently identified uric acid as one of these principal endogenous danger signals released from injured cells and mediating the immune response to antigens associated with injured cells (1). The molecular mechanism of this innate immune response to uric acid was further shown to be the result of the activation of the NALP3 inflammasome, a cytosolic, multiprotein complex that mediates caspase activation by uric acid crystals, leading to the production of the active forms of IL-1β and IL-18 (5). Recently, Kono et al. demonstrated in an in vivo hepatoxicity mouse model that uric acid is a physiological regulator of the inflammation induced by tissue injury (6). These data form the basis for our hypothesis that synovial fluid uric acid is a factor regulating tissue inflammation, disease severity, and progression in osteoarthritis (OA).Uric acid is best known for its role in gout. When uric acid concentrations exceed the limit of solubility (∼6.8 mg/dL or even lower under conditions of low pH or temperature), crystal formation can ensue, which is capable of activating the NALP3 inflammasome (5) and triggering the acute severe attacks of joint inflammation characteristic of gout (7). Several studies have previously posited an association o...

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Section: Discussionmentioning

confidence: 99%

Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Denoble¹,

Huffman²,

Stäbler³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

236

178

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“…In the last few years, uric acid has been vastly regarded as an alarmin of sterile inflammation because of the high cytosolic concentration (≈ 4 mg/mL) released upon cell death, which reacts with extracellular sodium to form MSU in the immediate vicinity of cellular injury (Shi et al 2003). Transport of MSU inside antigen-presenting cells through phagocytosis promotes its interaction with NALP3 inflammasome and induces IL-1β maturation and release thereby triggering an inflammatory response (Martinon et al 2006, Shi 2010. This is an important step in sterile inflammation that enables immune cells to sense injuries.…”

Section: Uric Acidmentioning

confidence: 99%

Sterile inflammation and pregnancy complications: a review

Nadeau-Vallée¹,

Obari²,

Palacios³

et al. 2016

Reproduction

219

161

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Inflammation is essential for successful embryo implantation, pregnancy maintenance and delivery. In the last decade, important advances have been made in regard to endogenous, and therefore non-infectious, initiators of inflammation, which can act through the same receptors as pathogens. These molecules are referred to as damage-associated molecular patterns (DAMPs), and their involvement in reproduction has only recently been unraveled. Even though inflammation is necessary for successful reproduction, untimely activation of inflammatory processes can have devastating effect on pregnancy outcomes. Many DAMPs, such as uric acid, high-mobility group box 1 (HMGB1), interleukin (IL)-1 and cell-free fetal DNA, have been associated with pregnancy complications, such as miscarriages, preeclampsia and preterm birth in preclinical models and in humans. However, the specific contribution of alarmins to these conditions is still under debate, as currently there is lack of information on their mechanism of action. In this review, we discuss the role of sterile inflammation in reproduction, including early implantation and pregnancy complications. Particularly, we focus on major alarmins vastly implicated in numerous sterile inflammatory processes, such as uric acid, HMGB1, IL-1α and cell-free DNA (especially that of fetal origin) while giving an overview of the potential role of other candidate alarmins.Reproduction (2016) 152 R277-R292

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“…In experimental models, cardiomyocyte growth and interstitial fibrosis are ascribed to activation of the reninangiotensin-aldosterone system; 7 UA activates the renin-angiotensin-aldosterone system both at the local and systemic levels. Hyperuricemia may act through indirect mechanisms as well, by promoting inflammation 8 and increasing oxidative status. 9 Large artery stiffness is both a marker and maker of hypertensive sequelae.…”

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confidence: 99%