Electronegative LDL induces priming and inflammasome activation leading to IL-1β release in human monocytes and macrophages

M. Estruch, K. Rajamäki, J. L. Sanchez-Quesada, P. T. Kovanen, K. Öörni, S. Benitez, J. Ordoñez-Llanos

Research output: Contribution to journalArticleResearchpeer-review

20 Citations (Scopus)

Abstract

© 2015 Elsevier B.V. All rights reserved. Background: Electronegative LDL (LDL(-)), a modified LDL fraction found in blood, induces the release of inflammatorymediators in endothelial cells and leukocytes. However, the inflammatory pathways activated by LDL(-) have not been fully defined.Weaimto study whether LDL(-) induced release of the first-wave proinflammatory IL-1ß in monocytes and monocyte-derived macrophages (MDM) and the mechanisms involved. Methods: LDL(-) was isolated from total LDL by anion exchange chromatography. Monocytes and MDM were isolated from healthy donors and stimulated with LDL(+) and LDL(-) (100 mg apoB/L). Results: Inmonocytes, LDL(-) promoted IL-1ß release in a time-dependent manner, obtaining at 20 h-incubation the double of IL-1ß release induced by LDL(-) than by native LDL. LDL(-)-induced IL-1ß release involved activation of the CD14-TLR4 receptor complex. LDL(-) induced priming, the first step of IL-1ß release, since it increased the transcription of pro-IL-1ß (8-fold) and NLRP3 (3-fold) compared to native LDL. Several findings show that LDL(-) induced inflammasome activation, the second step necessary for IL-1ß release. Preincubation ofmonocytes with K+ channel inhibitors decreased LDL(-)-induced IL-1ß release. LDL(-) induced formation of the NLRP3-ASC complex. LDL(-) triggered 2-fold caspase-1 activation compared to native LDL and IL-1ß release was strongly diminished in the presence of the caspase-1 inhibitor Z-YVAD. In MDM, LDL(-) promoted IL-1ß release, which was also associated with caspase-1 activation. Conclusions: LDL(-) promotes release of biologically active IL-1ß inmonocytes and MDM by induction of the two steps involved: priming and NLRP3 inflammasome activation. Significance: By IL-1ß release, LDL(-) could regulate inflammation in atherosclerosis.
Original languageEnglish
Pages (from-to)1442-1449
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1851
Issue number11
DOIs
Publication statusPublished - 4 Nov 2015

Keywords

  • Caspase-1
  • Electronegative LDL
  • Inflammasome
  • Interleukin-1ß
  • Macrophages
  • Monocytes

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