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, Aimée 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 journalArticlepeer-review

2 Scopus citations

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-1fl/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
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2019

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