Inflammasome Priming in Sterile Inflammatory Disease

Patel, Mitesh; Carroll, Richard G.; Galván-Peña, Silvia; Mills, Evanna L.; Olden, Robin; Triantafilou, Martha; Wolf, Amaya I.; Bryant, Clare E.; Triantafilou, Kathy; Masters, Seth L.

doi:10.1016/j.molmed.2016.12.007

Cited by 198 publications

(169 citation statements)

References 155 publications

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“…This is the first study demonstrating cholesterol crystal‐mediated NLRP3 activation in trophoblasts, as inflammasome responses have only been shown previously for uric acid, ATP and nigericin in these cells . NLRP3 inflammasome activation requires an already exaggerated inflammatory setting, as a priming signal is needed to achieve sufficient intracellular levels of NLRP3 and pro‐IL‐1β . The choice of priming signal in the placenta was based on reports of elevated C5a and TNF‐α in pre‐eclampsia , and supported by our discovery of C5a and TCC in the syncytium of pre‐eclamptic placentas.…”

Section: Discussionmentioning

confidence: 74%

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Stødle

Silva

Tangerås

et al. 2018

Clinical and Experimental Immunology

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Pre-eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger-sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod-like receptor protein (NLRP)3 inflammasome to release interleukin (IL)-1β and result in vigorous inflammation. We aimed to characterize crystal-induced NLRP3 activation in placental inflammation and examine its role in pre-eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre-eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C-reactive protein (hsCRP) and the pre-eclampsia marker soluble fms-like tyrosine kinase-1 (sFlt-1). The NLRP3 inflammasome pathway components (NLRP3, caspase-1, IL-1β) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co-expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL-1β and TCC was increased significantly and C5a-positive regions in the syncytiotrophoblast layer appeared more frequent in pre-eclamptic compared to normal pregnancies. In-vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement-primed crystal-induced release of IL-1β. This study confirms crystal-induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre-eclampsia.

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Section: Discussionmentioning

confidence: 74%

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Stødle

Silva

Tangerås

et al. 2018

Clinical and Experimental Immunology

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“…Caspase-1 in turn undergoes activation by a supramolecular assembly known as the inflammasome (Figure 3) (28,29). The inflammasome transduces inflammatory signals, culminating in cleavage of pro-caspase-1 to its active form, that in turn activates IL-1β.…”

Section: The Inflammasome Activates Interleukin-1βmentioning

confidence: 99%

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

Libby

2017

Journal of the American College of Cardiology

477

337

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Inflammatory pathways drive atherogenesis and link traditional risk factors to atherosclerosis and its complications. One inflammatory mediator has come to the fore as a therapeutic target in cardiovascular disease. The experimental and clinical evidence reviewed here support interleukin-1 beta (IL-1β) as both a local vascular and systemic contributor in this regard. Intrinsic vascular wall cells and lesional leukocytes alike can produce this cytokine. Local stimuli in the plaque favor the generation of active IL-1β through the action of a molecular assembly known as the inflammasome. Clinically applicable interventions that interfere with IL-1 action can improve cardiovascular outcomes, ushering in a new era of anti-inflammatory therapies for atherosclerosis. The translational path described here illustrates how advances in basic vascular biology may transform therapy. Biomarker-directed application of anti-inflammatory interventions promises to help us achieve a more precise and personalized allocation of therapy for our cardiovascular patients.

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“…This "priming" signal typically involves nuclear factor (NF)-kB activation induced by signaling through a tolllike receptor or other pattern recognition receptors (5). Pathogen-associated or hostderived factors may prime the inflammasome in non-sterile and sterile inflammatory diseases, respectively (6). The second signal promotes the functional activity of the NLRP3 inflammasome.…”

Section: ____________________________________________________________mentioning

confidence: 99%

High-density lipoprotein inhibits serum amyloid A–mediated reactive oxygen species generation and NLRP3 inflammasome activation

Shridas

Beer

Webb

2018

Journal of Biological Chemistry

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Serum amyloid A (SAA) is a high-density apolipoprotein whose plasma levels can increase more than 1000-fold during a severe acute-phase inflammatory response and are more modestly elevated in chronic inflammation. SAA is thought to play important roles in innate immunity, but its biological activities have not been completely delineated. We previously reported that SAA deficiency protects mice from developing abdominal aortic aneurysms (AAAs) induced by chronic angiotensin II (AngII) infusion. Here, we report that SAA is required for AngII-induced increases in interleukin-1 beta (IL-1β), a potent proinflammatory cytokine that is tightly controlled by the Nod-like receptor protein 3 (NLRP3) inflammasome and caspase-1 and has been implicated in both human and mouse AAAs. We determined that purified SAA stimulates IL-1β secretion in murine J774 and bone marrow-derived macrophages through a mechanism that depends on NLRP3 expression and caspase-1 activity, but is independent of P2X7 nucleotide receptor (P2X7R) activation. Inhibiting reactive oxygen species (ROS) by N-acetyl-Lcysteine or mito-TEMPO and inhibiting activation of cathepsin B by CA-074 blocked SAA-mediated inflammasome activation and IL-1β secretion. Moreover, inhibiting cellular potassium efflux with glyburide or increasing extracellular potassium also significantly reduced SAA-mediated IL-1β secretion. Of note, incorporating SAA into high-density lipid (HDL) prior to its use in cell treatments completely http://www.jbc.org/cgi

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Inflammasome Priming in Sterile Inflammatory Disease

Cited by 198 publications

References 155 publications

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts

Interleukin-1 Beta as a Target for Atherosclerosis Therapy

High-density lipoprotein inhibits serum amyloid A–mediated reactive oxygen species generation and NLRP3 inflammasome activation

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