Editors' ChoiceInflammation

Crystalline Danger Signal

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Science Signaling  04 May 2010:
Vol. 3, Issue 120, pp. ec129
DOI: 10.1126/scisignal.3120ec129

The NLRP3 inflammasome, which includes the pattern recognition receptor NLRP3 and the adaptor protein ASC, responds to potentially threatening endogenous and exogenous stimuli by activating caspase-1, which subsequently processes the cytokine interleukin-1 (IL-1) into its active form. Inflammation contributes to atherosclerosis; however, the primary inflammatory signal is unknown. Cholesterol can crystallize, and the NLRP3 inflammasome can be activated by crystals, but cholesterol crystals have been detected only in mature atherosclerotic lesions. By combining laser reflection and confocal microscopy, Duewell et al. were able to detect cholesterol crystals in early atherosclerotic lesions in aorta from apolipoprotein E–deficient mice on high-cholesterol diets. Formation of cholesterol crystals coincided with immune cell infiltration into the lesions. Human peripheral blood mononuclear cells or mouse macrophages released IL-1β when primed with lipopolysaccharide and subsequently incubated with cholesterol crystals; IL-1β secretion did not occur in unprimed cells and depended on the presence of NLRP3 and ASC as well as caspase-1 activity. Activation of the NLRP3 inflammasome by cholesterol crystals required phagocytosis, and various imaging techniques revealed that cholesterol crystals disrupted the phagolysosome. In wild-type mice, intraperitoneal injection of cholesterol crystals recruited neutrophils to the peritoneum. In contrast, neutrophil recruitment was reduced in mice lacking the IL-1 receptor, caspase-1, ASC, or NLRP3. Mice lacking the low-density lipoprotein receptor (LDLR) are susceptible to hypercholesterolemia on high-cholesterol diets. Irradiated LDLR-deficient mice reconstituted with bone marrow from NLRP3-, ASC-, or IL-1α− and IL-1β−deficient mice had smaller atherosclerotic lesions than those mice reconstituted with bone marrow from wild-type mice. Thus, cholesterol crystallization occurs earlier than previously suspected in atherosclerotic lesions and triggers the activation of the NLRP3 inflammasome.

P. Duewell, H. Kono, K. J. Rayner, C. M. Sirois, G. Vladimer, F. G. Bauernfeind, G. S. Abela, L. Franchi, G. Nuñez, M. Schnurr, T. Espevik, E. Lien, K. A. Fitzgerald, K. L. Rock, K. J. Moore, S. D. Wright, V. Hornung, E. Latz, NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464, 1357–1361 (2010). [PubMed]

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