, Volume 18, Issue 3, pp 271–285 | Cite as

Silica phagocytosis causes apoptosis and necrosis by different temporal and molecular pathways in alveolar macrophages

  • Gaurav N. Joshi
  • David A. KnechtEmail author
Original Paper


Chronic inhalation of crystalline silica is an occupational hazard that results in silicosis due to the toxicity of silica particles to lung cells. Alveolar macrophages play an important role in clearance of these particles, and exposure of macrophages to silica particles causes cell death and induction of markers of apoptosis. Using time-lapse imaging of MH-S alveolar macrophages, a temporal sequence was established for key molecular events mediating cell death. The results demonstrate that 80 % of macrophages die by apoptosis and 20 % by necrosis by clearly distinguishable pathways. The earliest detectable cellular event is phago-lysosomal leakage, which occurs between 30 and 120 min after particle uptake in both modes of death. Between 3 and 6 h later, cells undergoing apoptosis showed a dramatic increase in mitochondrial transmembrane potential, closely correlated with activation of both caspase-3 and 9 and cell blebbing. Externalization of phosphatidyl serine and nuclear condensation occurred 30 min–2 h after the initiation of cell blebbing. Cells undergoing necrosis demonstrated mitochondrial membrane depolarization but not hyperpolarization and no caspase activation. Cell swelling followed the decrease in mitochondrial membrane potential, distinguishing necrosis from apoptosis. All cells undergoing apoptosis followed the same temporal sequence, but the time lag between phago-lysosomal leakage and the other events was highly variable from cell to cell. These results demonstrate that crystalline silica exposure can result in either apoptosis or necrosis and each occurs in a well-defined but temporally variable order. The long time gap between phago-lysosomal leakage and hyperpolarization is not consistent with a simple scenario of phago-lysosomal leakage leading directly to cell death. The results highlight the importance of using a cell by cell time-lapse analysis to investigate a complex pathway such as silica induced cell death.


Silicosis Apoptosis Lysosome Mitochondria Caspase Necrosis 



We are thankful to Dr. Toru Kawanishi at NIHS, Japan and Dr. Gavin Welsh at University of Bristol, UK for their gift of Initiator and Effector FRET caspase probes. We are also thankful to Dr. Carol Norris at UConn microscopy facility for her assistance.

Supplementary material

10495_2012_798_MOESM1_ESM.eps (629 kb)
Supplementary material 1 (EPS 628 kb) Temporal variation in phago-lysosomal leakage between cells loaded with different size dextrans Release of dextran into the cytoplasm can occur at different times as shown by a cell which shows cytoplasmic 4 kD Fitc-dextran fluorescence early (panel A, 30 minutes) or late (panel B, 150 minutes). In cells loaded with 70 kD Fitc-dextran an increase in fluorescence was observed around silica particles as shown by arrows (C & D) indicative of an increase in the pH of the permeabilized phago-lysosome. Because 70 kD Fitc-dextran cannot enter nucleus the increase in fluorescence is only observed in the cytoplasm
10495_2012_798_MOESM2_ESM.eps (841 kb)
Supplementary material 2 (EPS 841 kb) Silica treated cells also show mitochondrial hyperpolarization when imaged using confocal microscopy Cells were labeled with TMRE, exposed to silica particles and imaged every 5 minutes to detect changes in mitochondria membrane potential (∆Ψm). Seven slices were captured at each time point and shown as a maximum Z projection. Mitochondria become hyperpolarized in cell 1 at 223 minutes remain hyperpolarized until 290 minutes and then depolarize. Cell 2 shows a similar pattern with hyperpolarization from at 385-485 minutes
10495_2012_798_MOESM3_ESM.mp4 (3.6 mb)
Supplementary material 3 (MP4 3705 kb) Cells show mitochondria hyperpolarization with cell blebbing upon exposure to silica MH-S cells labeled with TMRE and exposed to silica particles show mitochondrial hyperpolarization along with cell blebbing suggestive of apoptosis at 330 minutes. Mitochondrial depolarization occurs at 420 minutes followed by secondary necrosis
10495_2012_798_MOESM4_ESM.mp4 (6.9 mb)
Supplementary material 4 (MP4 7028 kb) Cells show mitochondria hyperpolarization when treated with Oligomycin MH-S cells labeled with TMRE and treated with a F1-F0 ATP’ase (complex V) inhibitor after 10 minute time point show a gradual increase in TMRE fluorescence from 11 minute onwards indicative of mitochondria hyperpolarization
10495_2012_798_MOESM5_ESM.mp4 (11.5 mb)
Supplementary material 5 (MP4 11726 kb) Cells show mitochondria depolarization when treated with FCCP MH-S cells were pre-labeled with TMRE, than at 1 minute a non-specific protonophore (FCCP) was added. Cells show a decrease in TMRE florescence within 2 minutes, indicative of mitochondria depolarization
10495_2012_798_MOESM6_ESM.mp4 (10.9 mb)
Supplementary material 6 (MP4 11190 kb) Cells show simultaneous mitochondrial hyperpolarization, cell blebbing and initiator caspase activation MH-S cells stably expressing caspase–9 FRET probe, treated with TMRE and exposed to silica show simultaneous mitochondrial hyperpolarization, cell blebbing and caspase -9 activation within a 5 minute window. Cell shows a gradual increase in mitochondria hyperpolarization and FRET ratio from 345 minute onwards that coincides cell blebbing. This cell also show a loss in TMRE fluorescence at 390 minutes, following which it starts to swell and undergo secondary necrosis. During this time a reduction in FRET ratio is also observed
10495_2012_798_MOESM7_ESM.mp4 (6.9 mb)
Supplementary material 7 (MP4 7051 kb) Cells show simultaneous mitochondria hyperpolarization, cell blebbing and effector caspase activation MH-S cells stably expressing caspase–3 FRET probe, treated with TMRE and exposed to silica show simultaneous mitochondrial hyperpolarization, cell blebbing and caspase-9 activation within a 5 minute window. Cell shows a sudden increase in TMRE fluorescence indicative of mitochondrial hyperpolarization and FRET ratio from 750 minutes onwards that coincides with cell blebbing
10495_2012_798_MOESM8_ESM.mp4 (1.3 mb)
Supplementary material 8 (MP4 1298 kb) Cells show Annexin V-FITC on plasma membrane post apoptosis Cells were exposed to silica in the presence of Annexin V-FITC to image accumulation of fluorescence on the plasma membrane. One cell retracts and starts to bleb at 279 minutes and become Annexin V positive at 330 minute whereas the other retracts and blebs at 330 minutes and becomes Annexin V positive at 420 minutes. The accumulation of plasma membrane fluorescence from Annexin V-FITC is lost as the cell progresses to secondary necrosis

Supplementary material 9 (MP4 519 kb) Cells undergoing apoptosis show nuclear condensation Cells labeled with nuclear dye Hoechst 33342 shows nuclear condensation at 420 minutes whereas cell blebbing was initiated at 300 minutes


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Molecular and Cell BiologyUniversity of ConnecticutStorrsUSA

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