image_2_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.PDF

Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

image_1_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.PDF

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

image_3_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.PDF

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

video_1_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.avi

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

video_3_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.avi

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

video_5_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.avi

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

Quantification of <i>in vivo</i> silica nanoparticle clearance.

Plot (z, t) of particles numbers (A) and area covered by particles (B) within the z-stack of Fig 1, over time. The stack starts with the alveolar wall close to the pleura (0 μm) and progresses towards the alveolar ducts (60 μm). Most particles are found close to the pleura (within alveoli). Particle number and area decrease within the 60 minutes time frame. The data indicates no movement from the alveoli towards the alveolar ducts, indicating that the particles do not leave the area via the airways. C: Quantification of particle clearance (data are mean ± SD, n = 3), with the reduction in agglomerate numbers in red and area in maximum intensity projection in blue. About half of the particles are cleared from the field of view over the first 30 minutes after exposure. The remainder of particles persist over the observation time of one hour. Significant changes are determined by student's t-test with Bonferroni adjusted p-values corrected for multiple comparisons (* p D: Whole organ imaging. Overlay of a white light image of the organs and a heat map-display of the fluorescence in liver (top), spleen (middle), and kidney (bottom) 24 h after instillation of Ø 50 nm Cy-7-labelled silica particles into the lung (right). The control images (left column) shows a low level of false positive counts in the liver.</p

Electron micrographs of low dose exposure (0.15 μg/g body weight) of silica nanoparticles in the lungs of mice.

Because particles were now individual rather that in agglomerates, we used ø 58 nm silica nanoparticle with 28 nm silver core for better visibility. After 1h, the lung was fixed and the left lower lobe sectioned for visualization. A: Particles between the epithelium and the endothelium, B,C: within the interstitium, D: inside a microvascular endothelial cell. E: Percentage of the alveolar epithelial cells (AECs) and of alveolar macrophages within TEM sections of mouse lungs that contained particles (0.15 μg/g body weight). Data are mean ± SD, from three mice per condition and three sections per mouse. Significant changes are determined by student's t-test (**** p < 0.0001). space bars: A-D = 100 nm.</p

video_4_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.avi

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p

video_2_Cholesterol Crystal-Mediated Inflammation Is Driven by Plasma Membrane Destabilization.avi

<p>Atherosclerosis is driven by an inflammatory milieu in the walls of artery vessels. Initiated early in life, it progresses to plaque formation and form cell accumulation. A culprit in this cascade is the deposition of cholesterol crystals (CC). The involvement of smaller crystals in the early stage of atherosclerotic changes may be critical to the long-term pathological development. How these small crystals initiate the pro-inflammatory events is under study. We report here an unexpected mechanism that microscopic CC interact with cellular membrane in a phagocytosis-independent manner. The binding of these crystals extracts cholesterol from the cell surface. This process causes a sudden catastrophic rupture of plasma membrane and necrosis of the bound cells independent of any known cell death-inducing pathways, releasing inflammatory agents associated with the necrotic cell death. Our results, therefore, reveal a biophysical aspect of CC in potentially mediating the inflammatory progress in atherosclerosis.</p