Uric Acid-Driven Th17 Differentiation Requires Inflammasome-Derived IL-1 and IL-18

Conforti-Andreoni, Cristina; Spreafico, Roberto; Qian, Hong; Riteau, Nicolas; Ryffel, Bernhard; Ricciardi‐Castagnoli, Paola; Mortellaro, Alessandra

doi:10.4049/jimmunol.1101408

Cited by 75 publications

(52 citation statements)

References 61 publications

(75 reference statements)

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“…180,181 Mice fed a high-fructose diet become obese and develop hyperuricaemia, which is associated with inflammasome activation, suggesting that uric acid also contributes to an inflammasome response in obesity induced by a high-fructose diet. 182 …”

Section: Mechanisms Of Hypertension In Obesitymentioning

confidence: 99%

The pathophysiology of hypertension in patients with obesity

2014

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The combination of obesity and hypertension is associated with high morbidity and mortality because it leads to cardiovascular and kidney disease. Potential mechanisms linking obesity to hypertension include dietary factors, metabolic, endothelial and vascular dysfunction, neuroendocrine imbalances, sodium retention, glomerular hyperfiltration, proteinuria, and maladaptive immune and inflammatory responses. Visceral adipose tissue also becomes resistant to insulin and leptin and is the site of altered secretion of molecules and hormones such as adiponectin, leptin, resistin, TNF and IL-6, which exacerbate obesity-associated cardiovascular disease. Accumulating evidence also suggests that the gut microbiome is important for modulating these mechanisms. Uric acid and altered incretin or dipeptidyl peptidase 4 activity further contribute to the development of hypertension in obesity. The pathophysiology of obesity-related hypertension is especially relevant to premenopausal women with obesity and type 2 diabetes mellitus who are at high risk of developing arterial stiffness and endothelial dysfunction. In this Review we discuss the relationship between obesity and hypertension with special emphasis on potential mechanisms and therapeutic targeting that might be used in a clinical setting.

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Section: Mechanisms Of Hypertension In Obesitymentioning

confidence: 99%

The pathophysiology of hypertension in patients with obesity

2014

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“…Bone marrow DCs, prepared as described (13), were primed with ultrapure LPS (0.1 mg/ml, Escherichia coli 055:B5; Alexis) in Opti-MEM medium (Life Technologies) for 3 h. Medium was replaced by adding normal baby rabbit serum as a source of complement (Cedarlane Laboratories) or monosodium urate (MSU; 250 mg/ml; Alexis) for 4 h. In some experiments, cells were preincubated with the caspase-1 inhibitor Z-YVAD-FMK after LPS priming. To inhibit MAC formation, normal rabbit complement (NRC) was preincubated with anti-C6 mAb (1.25 mg/ml, clone WU 6-4; Hycult), alone or with anti-C9 mAb (7.5 ng/ml), for 30 min at 37˚C before adding to DCs.…”

Section: Cell Culture and Stimulationmentioning

confidence: 99%

Cutting Edge: The NLRP3 Inflammasome Links Complement-Mediated Inflammation and IL-1β Release

Laudisi

Spreafico

Evrard

et al. 2013

The Journal of Immunology

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165

126

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The complement system is a potent component of the innate immune response, promoting inflammation and orchestrating defense against pathogens. However, dysregulation of complement is critical to several autoimmune and inflammatory syndromes. Elevated expression of the proinflammatory cytokine IL-1β is often linked to such diseases. In this study, we reveal the mechanistic link between complement and IL-1β secretion using murine dendritic cells. IL-1β secretion occurs following intracellular caspase-1 activation by inflammasomes. We show that complement elicits secretion of both IL-1β and IL-18 in vitro and in vivo via the NLRP3 inflammasome. This effect depends on the inflammasome components NLRP3 and ASC, as well as caspase-1 activity. Interestingly, sublethal complement membrane attack complex formation, but not the anaphylatoxins C3a and C5a, activated the NLRP3 inflammasome in vivo. These findings provide insight into the molecular processes underlying complement-mediated inflammation and highlight the possibility of targeting IL-1β to control complement-induced disease and pathological inflammation.

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“…This process involved the trapping of the crystals by extended aggregated NETs. Thus, although it is generally accepted that cMSU act pro-inflammatory through ligation of toll like receptors and subsequent activation of NF K B signaling383940, the pro-inflammatory effects of cMSU are reduced when these are entrapped within NETs. Of note, we found that DNase I only dismantled and dissolved UMA-containing aggregated NETs, whereas those composed of nsMSU were rather resistant to DNase I activity.…”

Section: Discussionmentioning

confidence: 99%

Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals

Pieterse

Jeremić

Czegley

et al. 2016

Sci Rep

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Hyperuricemia is strongly linked to cardiovascular complications including atherosclerosis and thrombosis. In individuals with hyperuricemia, needle-shaped monosodium urate crystals (nsMSU) frequently form within joints or urine, giving rise to gouty arthritis or renal calculi, respectively. These nsMSU are potent instigators of neutrophil extracellular trap (NET) formation. Little is known on the mechanism(s) that prevent nsMSU formation within hyperuricemic blood, which would potentially cause detrimental consequences for the host. Here, we report that complement proteins and fetuins facilitate the continuous clearance by blood-borne phagocytes and resident macrophages of small urate microaggregates (UMA; <1 μm in size) that initially form in hyperuricemic blood. If this clearance fails, UMA exhibit bipolar growth to form typical full-sized nsMSU with a size up to 100 μm. In contrast to UMA, nsMSU stimulated neutrophils to release NETs. Under conditions of flow, nsMSU and NETs formed densely packed DNase I-resistant tophus-like structures with a high obstructive potential, highlighting the importance of an adequate and rapid removal of UMA from the circulation. Under pathological conditions, intravascularly formed nsMSU may hold the key to the incompletely understood association between NET-driven cardiovascular disease and hyperuricemia.

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Uric Acid-Driven Th17 Differentiation Requires Inflammasome-Derived IL-1 and IL-18

Cited by 75 publications

References 61 publications

The pathophysiology of hypertension in patients with obesity

The pathophysiology of hypertension in patients with obesity

Cutting Edge: The NLRP3 Inflammasome Links Complement-Mediated Inflammation and IL-1β Release

Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals

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