MSU Crystals induce sterile IL-1β secretion via P2X7 receptor activation and HMGB1 release

Marinho, Ygor; Marques-da-Silva, Camila; Santana, Patrícia Teixeira; Chaves, Mariana M.; Tamura, Augusto Shuiti; Rangel, Thuany Prado; Gomes-e-Silva, Isabel Virgínia; Guimarães, Marília Zaluar P.; Coutinho‐Silva, Robson

doi:10.1016/j.bbagen.2019.129461

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…Our study showed that inhibition of P2X7R's function to block ATP-mediated activation of the NLRP3 inflammasome attenuated MSU crystal-induced AGA in rats, confirming the significance of ATP-P2X7R signaling in MSU crystal-induced AGA. This result was consistent with an in vitro study by Marinho et al, which reported that MSU crystal stimulationinduced IL-1β secretion was dependent on P2X7R's activation, an effect that corresponds to the extracellular concentration of ATP [31].…”

Section: Discussionsupporting

confidence: 93%

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis

Wan

Liu

et al. 2023

Oxidative Medicine and Cellular Longevity

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Activation of the nod-like receptor protein 3 (NLRP3) inflammasome by monosodium urate (MSU) crystals has been identified as the molecular basis for the acute inflammatory response in gouty arthritis. However, MSU crystals alone are not sufficient to induce acute gouty arthritis (AGA). Adenosine triphosphate (ATP) is an endogenous signaling molecule involved in the NLRP3 inflammasome activation. We aimed to explore the role of ATP in MSU crystal-induced AGA development. In peripheral blood mononuclear cell-derived macrophages obtained from gout patients, we observed a synergistic effect of ATP on MSU crystal-induced IL-1β release. Furthermore, in a rat model of spontaneous gout, we demonstrated that a synergistic effect of ATP and MSU crystals, but not MSU crystals alone, is essential for triggering AGA. Mechanistically, this synergistic effect is achieved through the purinergic receptor P2X7 (P2X7R). Blockade of P2X7R prevented AGA induction in rats after local injection of MSU crystals, and carrying the mutant hP2X7R gene contributed to the inhibition of NLRP3 inflammasome activation induced by costimulation of MSU crystals and ATP in vitro. Taken together, these results support the synergistic effect of ATP on MSU crystal-induced NLRP3 inflammasome activation facilitating inflammatory episodes in AGA. In this process, P2X7R plays a key regulatory role, suggesting targeting P2X7R to be an attractive therapeutic strategy for the treatment of AGA.

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Section: Discussionsupporting

confidence: 93%

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis

Wan

Liu

et al. 2023

Oxidative Medicine and Cellular Longevity

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“…The role of P2X7R in the IL-1 β maturation via NLRP3 inflammasome assembly in both infectious and inflammatory disorders is currently accepted [ 16 , 28 , 29 ]. Jin et al [ 10 ] also proposed a P2Y 2 R-mediated inflammasome activation pathway [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

P2Y2 Receptor Induces L. amazonensis Infection Control in a Mechanism Dependent on Caspase-1 Activation and IL-1β Secretion

Thorstenberg

Martins

Figliuolo

et al. 2020

Mediators of Inflammation

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Leishmaniasis is a neglected tropical disease caused by an intracellular parasite of the genus Leishmania. Damage-associated molecular patterns (DAMPs) such as UTP and ATP are released from infected cells and, once in the extracellular medium, activate P2 purinergic receptors. P2Y2 and P2X7 receptors cooperate to control Leishmania amazonensis infection. NLRP3 inflammasome activation and IL-1β release resulting from P2X7 activation are important for outcomes of L. amazonensis infection. The cytokine IL-1β is required for the control of intracellular parasites. In the present study, we investigated the involvement of the P2Y2 receptor in the activation of NLRP3 inflammasome elements (caspase-1 and 11) and IL-1β secretion during L. amazonensis infection in peritoneal macrophages as well as in a murine model of cutaneous leishmaniasis. We found that 2-thio-UTP (a selective P2Y2 agonist) reduced parasite load in L. amazonensis-infected murine macrophages and in the footpads and lymph nodes of infected mice. The antiparasitic effects triggered by P2Y2 activation were not observed when cells were pretreated with a caspase-1 inhibitor (Z-YVAD-FMK) or in macrophages from caspase-1/11 knockout mice (CASP-1,11−/−). We also found that UTP treatment induced IL-1β secretion in wild-type (WT) infected macrophages but not in cells from CASP-1,11−/− mice, suggesting that caspase-1 activation by UTP triggers IL-1β secretion in L. amazonensis-infected macrophages. Infected cells pretreated with IL-1R antagonist did not show reduced parasitic load after UTP and ATP treatment. Our in vivo experiments also showed that intralesional UTP treatment reduced both parasite load (in the footpads and popliteal lymph nodes) and lesion size in wild-type (WT) and CASP-11−/− but not in CASP-1,11−/− mice. Taken together, our findings suggest that P2Y2R activation induces CASP-1 activation and IL-1β secretion during L. amazonensis infection. IL-1β/IL-1R signaling is crucial for P2Y2R-mediated protective immune response in an experimental model of cutaneous leishmaniasis.

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“…NLRP3 inflammasome activates cysteinyl aspartate specific proteinase-1 (caspase-1) that cleaves pro-IL-1 β to produce IL-1 β ( Wu et al, 2019a ). Further, extracellular ATP activates P2X7 receptor 7 (P2X7R) in macrophages and sets off potassium ion outflow, causing the NLRP3 inflammasome to release IL-1 β ( Alessandra Piccini et al, 2008 ; Marinho et al, 2020 ). IL-1 β promotes the release of various inflammatory mediators, including TNF- α , interleukin-1(IL-1), IL-6, and IL-8.…”

Section: Survey Methodologymentioning

confidence: 99%

The biomarkers discovery of hyperuricemia and gout: proteomics and metabolomics

You

2022

PeerJ

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Background Hyperuricemia and gout are a group of disorders of purine metabolism. In recent years, the incidence of hyperuricemia and gout has been increasing, which is a severe threat to people’s health. Several studies on hyperuricemia and gout in proteomics and metabolomics have been conducted recently. Some literature has identified biomarkers that distinguish asymptomatic hyperuricemia from acute gout or remission of gout. We summarize the physiological processes in which these biomarkers may be involved and their role in disease progression. Methodology We used professional databases including PubMed, Web of Science to conduct the literature review. This review addresses the current landscape of hyperuricemia and gout biomarkers with a focus on proteomics and metabolomics. Results Proteomic methods are used to identify differentially expressed proteins to find specific biomarkers. These findings may be suggestive for the diagnosis and treatment of hyperuricemia and gout to explore the disease pathogenesis. The identified biomarkers may be mediators of the link between hyperuricemia, gout and kidney disease, metabolic syndrome, diabetes and hypertriglyceridemia. Metabolomics reveals the main influential pathways through small molecule metabolites, such as amino acid metabolism, lipid metabolism, or other characteristic metabolic pathways. These studies have contributed to the discovery of Chinese medicine. Some traditional Chinese medicine compounds can improve the metabolic disorders of the disease. Conclusions We suggest some possible relationships of potential biomarkers with inflammatory episodes, complement activation, and metabolic pathways. These biomarkers are able to distinguish between different stages of disease development. However, there are relatively few proteomic as well as metabolomic studies on hyperuricemia and gout, and some experiments are only primary screening tests, which need further in-depth study.

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MSU Crystals induce sterile IL-1β secretion via P2X7 receptor activation and HMGB1 release

Cited by 15 publications

References 36 publications

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis

P2X7R Mediates the Synergistic Effect of ATP and MSU Crystals to Induce Acute Gouty Arthritis

P2Y2 Receptor Induces L. amazonensis Infection Control in a Mechanism Dependent on Caspase-1 Activation and IL-1β Secretion

The biomarkers discovery of hyperuricemia and gout: proteomics and metabolomics

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