Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

By K. Rajamäki, J. Lappalainen, K. Öörni, E. Välimäki, S. Matikainen, P. Kovanen, K. Eklund. PLoS ONE, 2010

1,010 citations recorded by the source corpus.

Background Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1β and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1β has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway. Principal Findings Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1β from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1β was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1β secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1β secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization. Conclusions The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.

Subfields: Molecular Biology, Public Health, Environmental and Occupational Health, Surgery

View Paper: https://www.semanticscholar.org/paper/fa6cd20e147dd066a3358c77aa3fc9b4dc9ff451

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In Molecular Biology

1. Peter Libby
2. A. Lichtman
3. P. Ridker
4. K. Moore
5. Christian Weber
6. Kate Schroder
7. G. Hansson
8. E. Latz

In Public Health, Environmental and Occupational Health

1. Peter Libby
2. Kate Schroder
3. I. Tabas

In Surgery

1. I. Tabas
2. Peter Libby
3. G. Hansson
4. A. Lichtman
5. P. Ridker
6. T. Thuren
7. A. Zalewski
8. Kate Schroder

Citations in the corpus

• Age and Age-Related Diseases: Role of Inflammation Triggers and Cytokines (2018, background): “Lyosomal destabilization is also associated with NLRP3 activation and can be induced by a number of molecules, including cholesterol crystals in macrophages linking atherosclerosis progression with inflammation (142).”
• CD36 coordinates NLRP3 inflammasome activation by facilitating the intracellular nucleation from soluble to particulate ligands in sterile inflammation (2013, background): “In the AD brain and diabetic pancreas, amyloid plaques arise from the aggregation of pre-fibrillar amyloidogenic peptides such as the Aβ(1-42) peptide17, 18, 19 or IAPP20, 21, 22, which oligomerize and give rise to higher order structures, including fibrils.”
• NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice (2017, methodology): “Cholesterol crystal preparation Hydrated cholesterol crystals, prepared as described [24], were homogenized to obtain crystals <10 m in diameter, and suspended in culture media before addition to cells.”
• The Cellular Biology of Macrophages in Atherosclerosis (2011, positive): “Cholesterol crystal-induced macrophage inflammation involves phagolysosomal disruption, inflammasome components, and the lysosomal proteases cathepsin B and cathepsin L (Duewell et al., 2010; Rajamäki et al., 2010).”
• NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. (2018, result): “role for CC-mediated NLRP3 inflammasome activation and subsequent IL-1β secretion in the development and progression of atherosclerosis.(25,26) Comparable to other previously known”
• Interleukin-1β inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). (2011, background): “Moreover, recent studies have shown that the NLRP3 inflammasome critical for production of active IL-1β responds not only by bacteria, crystalline uric acid, and crystalline pyrophosphate but also to cholesterol crystals and minimally modified LDL cholesterol.(62,63) This observation further implica”
• Immune Effector Mechanisms Implicated in Atherosclerosis: From Mice to Humans (2013, background): “…can activate a member of the cytosolic-nucleotide binding domain and leucine-rich repeat gene family (NLRP3), activating its associated inflammasome, and promote processing of the proform of interleukin-1b (IL-1b) into a bioactive cytokine (Duewell et al., 2010; Rajamäki et al., 2010).”
• Atherosclerosis: current pathogenesis and therapeutic options (2011, background): “An intriguing finding is the presence of small cholesterol crystals in human and mouse atherosclerotic lesion”