Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis.
OBJECTIVE:Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also importa...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3958341?pdf=render |
| _version_ | 1818042329347391488 |
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| author | Matthew C Exline Steven Justiniano Jennifer L Hollyfield Freweine Berhe Beth Y Besecker Srabani Das Mark D Wewers Anasuya Sarkar |
| author_facet | Matthew C Exline Steven Justiniano Jennifer L Hollyfield Freweine Berhe Beth Y Besecker Srabani Das Mark D Wewers Anasuya Sarkar |
| author_sort | Matthew C Exline |
| collection | DOAJ |
| description | OBJECTIVE:Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles (MVs) containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis.. DESIGN:Single-center cohort study. MEASUREMENTS:50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3. MAIN RESULTS:Septic patients had higher microvesicular caspase-1 activity 0.05 (0.04, 0.07) AFU versus 0.0 AFU (0, 0.02) (p<0.001) on day 1 and this persisted on day 3, 0.12 (0.1, 0.2) versus 0.02 (0, 0.1) (p<0.001). MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients (17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001) and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis. CONCLUSION:These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles. |
| first_indexed | 2024-12-10T08:44:35Z |
| format | Article |
| id | doaj.art-f8422bb0604347e286ea8439425b47f2 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T08:44:35Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f8422bb0604347e286ea8439425b47f22022-12-22T01:55:46ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0193e9096810.1371/journal.pone.0090968Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis.Matthew C ExlineSteven JustinianoJennifer L HollyfieldFreweine BerheBeth Y BeseckerSrabani DasMark D WewersAnasuya SarkarOBJECTIVE:Immune dysregulation during sepsis is poorly understood, however, lymphocyte apoptosis has been shown to correlate with poor outcomes in septic patients. The inflammasome, a molecular complex which includes caspase-1, is essential to the innate immune response to infection and also important in sepsis induced apoptosis. Our group has recently demonstrated that endotoxin-stimulated monocytes release microvesicles (MVs) containing caspase-1 that are capable of inducing apoptosis. We sought to determine if MVs containing caspase-1 are being released into the blood during human sepsis and induce apoptosis.. DESIGN:Single-center cohort study. MEASUREMENTS:50 critically ill patients were screened within 24 hours of admission to the intensive care unit and classified as either a septic or a critically ill control. Circulatory MVs were isolated and analyzed for the presence of caspase-1 and the ability to induce lymphocyte apoptosis. Patients remaining in the ICU for 48 hours had repeated measurement of caspase-1 activity on ICU day 3. MAIN RESULTS:Septic patients had higher microvesicular caspase-1 activity 0.05 (0.04, 0.07) AFU versus 0.0 AFU (0, 0.02) (p<0.001) on day 1 and this persisted on day 3, 0.12 (0.1, 0.2) versus 0.02 (0, 0.1) (p<0.001). MVs isolated from septic patients on day 1 were able to induce apoptosis in healthy donor lymphocytes compared with critically ill control patients (17.8±9.2% versus 4.3±2.6% apoptotic cells, p<0.001) and depletion of MVs greatly diminished this apoptotic signal. Inhibition of caspase-1 or the disruption of MV integrity abolished the ability to induce apoptosis. CONCLUSION:These findings suggest that microvesicular caspase-1 is important in the host response to sepsis, at least in part, via its ability to induce lymphocyte apoptosis. The ability of microvesicles to induce apoptosis requires active caspase-1 and intact microvesicles.http://europepmc.org/articles/PMC3958341?pdf=render |
| spellingShingle | Matthew C Exline Steven Justiniano Jennifer L Hollyfield Freweine Berhe Beth Y Besecker Srabani Das Mark D Wewers Anasuya Sarkar Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. PLoS ONE |
| title | Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. |
| title_full | Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. |
| title_fullStr | Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. |
| title_full_unstemmed | Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. |
| title_short | Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis. |
| title_sort | microvesicular caspase 1 mediates lymphocyte apoptosis in sepsis |
| url | http://europepmc.org/articles/PMC3958341?pdf=render |
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