Low human and murine Mcl-1 expression leads to a pro-apoptotic plaque phenotype enriched in giant-cells

Margaux A. C. Fontaine, Marijke M. Westra, Ilze Bot, Han Jin, Aimee J. P. M. Franssen, Martine Bot, Saskia C. A. de Jager, Ivan Dzhagalov, You-Wen He, Bart J. M. van Vlijmen, Marion J. J. Gijbels, Chris P. Reutelingsperger, Theo J. C. van Berkel, Judith C. Sluimer, Lieve Temmerman*, Erik A. L. Biessen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Web of Science)

Abstract

The anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) plays an important role in survival and differentiation of leukocytes, more specifically of neutrophils. Here, we investigated the impact of myeloid Mcl-1 deletion in atherosclerosis. Western type diet fed LDL receptor-deficient mice were transplanted with either wild-type (WT) or LysMCre Mcl-(fl/fl) (Mcl-1(-/-)) bone marrow. Mcl-1 myeloid deletion resulted in enhanced apoptosis and lipid accumulation in atherosclerotic plaques. In vitro, Mcl-1 deficient macrophages also showed increased lipid accumulation, resulting in increased sensitivity to lipid-induced cell death. However, plaque size, necrotic core and macrophage content were similar in Mcl-1(-/-) compared to WT mice, most likely due to decreased circulating and plaque-residing neutrophils. Interestingly, Mcl-1(-/-) peritoneal foam cells formed up to 45% more multinucleated giant cells (MGCs) in vitro compared to WT, which concurred with an increased MGC presence in atherosclerotic lesions of Mcl-1(-/-) mice. Moreover, analysis of human unstable atherosclerotic lesions also revealed a significant inverse correlation between MGC lesion content and Mcl-1 gene expression, coinciding with the mouse data. Taken together, these findings suggest that myeloid Mcl-1 deletion leads to a more apoptotic, lipid and MGC-enriched phenotype. These potentially pro-atherogenic effects are however counteracted by neutropenia in circulation and plaque.

Original languageEnglish
Article number14547
Number of pages11
JournalScientific Reports
Volume9
DOIs
Publication statusPublished - 10 Oct 2019

Keywords

  • ATHEROSCLEROTIC PLAQUES
  • MACROPHAGES
  • NEUTROPHILS
  • DEATH
  • BCL-2
  • INDUCTION
  • ARTERIES
  • PROTEIN

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