Oxidatively modified phosphatidylserines on the surface of apoptotic cells are essential phagocytic 'eat-me' signals: cleavage and inhibition of phagocytosis by Lp-PLA2

Details

• Personal Author:
  Balasubramanian K ; He RR ; Kagan VE ; Kapralov AA ; Macphee CH ; Tyurin VA ; Tyurina YY ; Vikulina AS ; Winnica D
• Description:
  Diversified anionic phospholipids, phosphatidylserines (PS), externalized to the surface of apoptotic cells are universal phagocytic signals. However, the role of major PS metabolites, such as peroxidized species of PS (PSox) and lyso-PS, in the clearance of apoptotic cells has not been rigorously evaluated. Here, we demonstrate that H2O2 was equally effective in inducing apoptosis and externalization of PS in naive HL60 cells and in cells enriched with oxidizable polyunsaturated species of PS (supplemented with linoleic acid (LA)). Despite this, the uptake of LA-supplemented cells by RAW264.7 and THP-1 macrophages was more than an order of magnitude more effective than that of naive cells. A similar stimulation of phagocytosis was observed with LA-enriched HL60 cells and Jurkat cells triggered to apoptosis with staurosporine. This was due to the presence of PSox on the surface of apoptotic LA-supplemented cells (but not of naive cells). This enhanced phagocytosis was dependent on activation of the intrinsic apoptotic pathway, as no stimulation of phagocytosis occurred in LA-enriched cells challenged with Fas antibody. Incubation of apoptotic cells with lipoprotein-associated phospholipase A2 (Lp-PLA2), a secreted enzyme with high specificity towards PSox, hydrolyzed peroxidized PS species in LA-supplemented cells resulting in the suppression of phagocytosis to the levels observed for naive cells. This suppression of phagocytosis by Lp-PLA2 was blocked by a selective inhibitor of Lp-PLA2, SB-435495. Screening of possible receptor candidates revealed the ability of several PS receptors and bridging proteins to recognize both PS and PSox, albeit with diverse selectivity. We conclude that PSox is an effective phagocytic 'eat-me' signal that participates in the engulfment of cells undergoing intrinsic apoptosis. [Description provided by NIOSH]
• Subjects:
  Energy Metabolism Esters Lipids Occupational Health Peroxides Safety
• Keywords:
  Apoptosis Author Keywords: Oxidative Stress Cell-differentiation Cell-metabolism Cellular-reactions Drug-interaction Humans Inflammation Lipoprotein-associated Phospholipase Metabolism Metabolites Oxidation-reduction-reactions Oxidative-phosphorylation Oxidized Phosphatidylserines Phagocytes Phagocytic-activity Phagocytosis Pharmacology Phosphatidylserines Phospholipids Physiological-effects Proteins

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• ISSN:
  1350-9047
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Journal Article
• Place as Subject:
  OSHA Region 3 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health
• Location:
  North America
• Volume:
  21
• Issue:
  5
• NIOSHTIC Number:
  nn:20045619
• Citation:
  Cell Death Differ 2014 May; 21(5):825-835
• Contact Point Address:
  V.A. Tyurin, Environmental and Occupational Health, University of Pittsburgh, 100 Technology Drive, Suite 350, Pittsburgh, PA 15260, USA
• CAS Registry Number:
  Hydrogen peroxide (CAS RN 7722-84-1)
• Federal Fiscal Year:
  2014
• NORA Priority Area:
  Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  True
• Start Date:
  20050701
• Source Full Name:
  Cell Death and Differentiation
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:3aafe29cff072a43566ced7a11e1448ff5db709993913177ceb637e0d1da549c26f457a141b899d53d0b679e13644265c3af398b5db81731a89ebc08e07f6f2c
• Download URL:
  https://stacks.cdc.gov/view/cdc/200972/cdc_200972_DS1.pdf
• File Type:
  [PDF - 1.76 MB ]