NLRP3 inflamasomes are required for atherogenesis and activated by cholesterol crystals that form early in disease

By P. Duewell, H. Kono, K. Rayner, C. Sirois, G. Vladimer, F. Bauernfeind, G. Abela, L. Franchi, G. Núñez, M. Schnurr and 8 more. Nature, 2010

2,600 citations recorded by the source corpus.

The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1α/β-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

Subfields: Immunology, Molecular Biology, Surgery

View Paper: https://www.semanticscholar.org/paper/7566861d58e641988aa6e38d486e3a0b7598127a

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The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Peter Libby
2. I. Tabas
3. A. Lichtman
4. Guido Kroemer
5. G. Hansson
6. L. Galluzzi
7. K. Moore
8. Klaus Ley

In Molecular Biology

1. Guido Kroemer
2. L. Galluzzi
3. Douglas R. Green
4. Peter Libby
5. A. Lichtman
6. K. Moore
7. G. Hansson
8. I. Tabas

In Surgery

1. I. Tabas
2. A. Lichtman
3. G. Hansson
4. Peter Libby
5. Guido Kroemer
6. Klaus Ley
7. K. Moore
8. Joachim L. Schultze

Citations in the corpus

• Metabolic control of cell death (2014, background): “A number of clinically relevant stimuli, including monosodium urate crystals (associated with gout) (36), calcium pyrophosphage dihydrate crystals (associated with pseudogout) (36), and cholesterol crystals (associated with atherosclerosis) (37), activate the NLRP3 inflammasome through a mechanism t”
• NLRP3 inflammasome: From a danger signal sensor to a regulatory node of oxidative stress and inflammatory diseases (2015, neutral): “…. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 302 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304”
• The immune system in atherosclerosis (2011, background): “The NLRP3 (also known as NALP3) inflammasome has been reported to be activated by cholesterol crystals present in macrophage”
• Cytokines in Inflammatory Disease (2019, background): “reported decreased development of atherosclerotic lesions in mice lacking inflammasome related molecules NLRP3, ASC or IL-1α/β and showed that cholesterol crystals as a possible DAMP strongly activated NLRP3 inflammasomes in macrophages [81].”
• Immunity and Inflammation in atherosclerosis (2019, background): “A clinically important consequence of cholesterol loading is the formation of intracellular cholesterol microcrystals that activate the inflammasome, a molecular machinery comprising molecules of the cytosolic nucleotide binding domain and leucine-rich repeat gene family (NLRP3) that cleaves pro-IL ”
• Canonical Nlrp3 inflammasome links systemic low grade inflammation to functional decline in aging (2013, positive): “…activation has been implicated in chronic diseases such as Alzheimer’s diseases (Heneka et al., 2013), diabetes (Masters et al., 2010; Vandanmagsar et al., 2011; Wen et al., 2011; Youm et al., 2011), athero- Cell sclerosis (Duewell et al., 2010), arthritis, and gout (Martinon et al., 2006).”
• Pathophysiology of Atherosclerosis (2022, background): “Cholesterol crystals activate NLRP3 inflammasome through lysosomal damage [255].”
• Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming (2018, methodology): “We chose to study the effects of WD after 4 weeks feeding since at this early time point only minimal atherosclerotic lesions can be observed (Duewell et al., 2010), and thus a contribution of plaque-derived immune cells and potential anti-inflammatory effects during plaque regression is minimized.”
• Monocyte-Macrophages and T Cells in Atherosclerosis (2017, positive): “Although cholesterol crystals have been implicated in this process (Duewell et al., 2010; Sheedy et al., 2013), other mechanisms are likely to contribute as well (Hoseini et al., 2017).”