NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals
(Impact Factor: 41.46).
04/2010; 464(7293):1357-61. DOI: 10.1038/nature08938
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-1alpha/beta-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.
Available from: jmm.sgmjournals.org
- "About four decades ago, virus-induced cholesterol crystals were observed in cultured cells, and such crystals are known to form when cholesterol accumulates in the plaque and to activate inflammasomes (Fabricant et al., 1973; Duewell et al., 2010). Moreover viral infection was shown to induce experimental atherosclerosis and also to alter aortic cholesterol metabolism and accumulation (Fabricant et al., 1978; Hajjar et al., 1986). "
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ABSTRACT: Cardiovascular disease is still the major cause of death worldwide despite the remarkable progress in its prevention and treatment. Endothelial progenitor cells have recently emerged as key players of vascular repair and regenerative medicine applied to cardiovascular disease. A large amount of effort has been put into discovering the factors that could aid or impair the number and function of endothelial progenitor cells, and also characterizing at molecular level these cells in order to facilitate their therapeutic applications in vascular disease. Interestingly, the major cardiovascular risk factors have been associated with reduced number and function of endothelial progenitor cells. The bacterial contribution cardiovascular disease represents a long-standing controversy. The discovery that Bartonella henselae can infect and damage endothelial progenitor cells revitalizes the enduring controversy about the microbiological contribution to atherosclerosis, thus allowing the hypothesis that this infection could impair the cardiovascular regenerative potential increasing the risk for cardiovascular disease. In this review, we summarize the rationale to suggest that Bartonella henselae could favor atherogenesis by infecting and damaging endothelial progenitor cells, thus reducing their vascular repair potential. These mechanisms suggest a novel link between communicable and non-communicable human diseases, and put forward the possibility that Bartonella henselae could enhance the susceptibility and worsen the prognosis in cardiovascular disease.
Journal of Medical Microbiology 06/2015; 64(8). DOI:10.1099/jmm.0.000099 · 2.25 Impact Factor
Available from: PubMed Central
- "In addition, there is ample evidence of inflammasome activation in atherosclerotic lesions, and IL-1 likely plays an important role in early atherogenesis (Lu and Kakkar, 2014). Based on in vitro studies and in vivo observations, a leading hypothesis posits that cholesterol microcrystals derived from the cellular ingestion of retained LPs activate the inflammasome pathway (Duewell et al., 2010). However, it is not clear whether cholesterol crystallization would be robust enough at body temperature to activate the inflammasome pathway, and so other mechanisms of are being explored. "
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ABSTRACT: Atherosclerosis occurs in the subendothelial space (intima) of medium-sized arteries at regions of disturbed blood flow and is triggered by an interplay between endothelial dysfunction and subendothelial lipoprotein retention. Over time, this process stimulates a nonresolving inflammatory response that can cause intimal destruction, arterial thrombosis, and end-organ ischemia. Recent advances highlight important cell biological atherogenic processes, including mechanotransduction and inflammatory processes in endothelial cells, origins and contributions of lesional macrophages, and origins and phenotypic switching of lesional smooth muscle cells. These advances illustrate how in-depth mechanistic knowledge of the cellular pathobiology of atherosclerosis can lead to new ideas for therapy.
© 2015 Tabas et al.
The Journal of Cell Biology 04/2015; 209(1):13-22. DOI:10.1083/jcb.201412052 · 9.83 Impact Factor
Available from: Norbert Suttorp
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ABSTRACT: Listeria monocytogenes is an intracellular, Gram-positive bacterium that can cause life-threatening illness especially in immunocompromised individuals and newborns. The pathogen propagates within the cytosol of various host cells after escaping from the phagosomal compartment depending on the cytolysin listeriolysin O. While L. monocytogenes can manipulate the endocytic and many host-cell signaling cascades to its advantage, host cells are however capable of detecting Listeria infection at different cellular compartments by expressing innate immune receptors that trigger antibacterial defense pathways. These receptors include the Toll-like receptors, NOD-like receptors (NLRs), and cytosolic DNA sensors. Some NLRs as well as the DNA sensor AIM2 form multiprotein complexes called inflammasomes. Inflammasomes regulate caspase-1-dependent production of the key inflammatory cytokines IL-1β and IL-18 as well as pyroptotic cell death in L. monocytogenes-infected cells. This review describes the current knowledge about innate immune sensing and inflammasome activation in Listeria infection.
Frontiers in Microbiology 01/2010; 1:149. DOI:10.3389/fmicb.2010.00149 · 3.99 Impact Factor
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