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Introduction
The purinergic 2X7 receptor (P2X7R) is significantly expressed in CD31+ endothelial cells and CD68+ macrophages in atherosclerotic lesions in human carotid arteries (1). P2X7R may also modulate the release of several cytokines known to promote atherosclerosis, including interleukin (IL)-1β, IL-6 and tumor necrosis factor α through immune cells (2). Although this evidence suggests that there is an association between P2X7R and the development of atherosclerosis, the mechanisms through which P2X7R promotes the production of mature IL-1β by macrophages by modulating the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome remain unknown.
P2X7R has attracted the most attention out of all the purinergic receptor family members, as it is involved in the inflammatory response by modulating the production of cytokines (such as IL-1β) by immune cells (2). However, the caspase-1 hydrolysis-dependent proIL-1β maturation also relies on NLRP3 inflammasome activity (7,8).
NLRP3 inflammasomes are known as cytoplasmic pattern recognition receptors (PRRs) (3,4). NLRP3 interacts with the adaptor molecule ASC (also known as PYD and CARD domain containing PYCARD) and caspase-1 to form a large multiprotein complex known as the NLRP3 inflammasome. Pro-caspase-1 is then converted into active caspase-1, which hydrolyzes proIL-1β into active IL-1β (5). The NLRP3 inflammasome can be activated by a wide range of stimuli, including intracellular cholesterol crystals (6,7), uric acid crystals (8,9), extracellular amyloids (10,11), adenosine triphosphate (ATP) (9,12,13), silicon dioxide and aluminum salts (14,15). A number of extracellular substances activate the NLRP3 inflammasome through P2X7R located on the plasma membrane (16,17).
In vitro studies have demonstrated that cholesterol crystals can activate the NLRP3 inflammasome and promote the release of IL-1β by macrophages with the assistance of lipopolysaccharides (LPS) (7,8). This is mainly due to the fact that IL-1β production involves a complex process and requires two independent signals (18,19). The first signal induces IL-1β mRNA expression through the Toll-like receptor 4 (TLR4) pathway, which is required for proIL-1β synthesis. The second signal is the lysozyme-dependent NLRP3 inflammasome activation and active caspase-1 production (8). Unlike LPS, cholesterol crystals cannot activate TLR4 signaling. Therefore, cholesterol crystals can only induce IL-1β production with the assistance of LPS (7,8). However, to the best of our knowledge, at present, evidence proving the high level of LPS in the plasma of patients with coronary...