title: Microvesicular caspase-1 mediates lymphocyte apoptosis in sepsis.
abstract: 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..
  
  
  METHODS
  Single-center cohort study.
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Exline
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Steven
authors.initials: S
authors.lastname: Justiniano
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Hollyfield
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Freweine
authors.initials: F
authors.lastname: Berhe
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Besecker
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Srabani
authors.initials: S
authors.lastname: Das
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Wewers
authors.affiliation: Davis Heart and Lung Research Institute, Pulmonary, Allergy, Critical Care and Sleep Medicine Division, Wexner Medical Center, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Anasuya
authors.initials: A
authors.lastname: Sarkar
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D020170:Caspase 1 / Q000378:metabolism / Q000494:pharmacology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D055252:Cell-Derived Microparticles / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D015331:Cohort Studies; D016638:Critical Illness; D005260:Female; D006801:Humans; D007362:Intensive Care Units; D008214:Lymphocytes / Q000187:drug effects* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018805:Sepsis / Q000097:blood / Q000201:enzymology* / Q000473:pathology
chemical_list: D061945:Caspase Inhibitors; D020170:Caspase 1