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

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.

The hypoxia-sensor carbonic anhydrase IX affects macrophage metabolism, but is not a suitable biomarker for human cardiovascular disease

“…www.nature.com/scientificreports/ Lipid uptake. Isolation of LDL and subsequent oxidation into oxLDL is described elsewhere 46 . Post-dialysis oxLDL concentration was determined using the bicinchoninic acid (BCA) protein assay kit (Pierce, 23227).…”

Altered Neutrophil Responses to Dengue Virus Serotype Three: Delayed Apoptosis is Regulated by Stabilisation of Mcl-1

“…Therefore, this study aimed to identify how dengue virus serotype three (DV3) affects neutrophil viability and function over time. Our ndings reveal that DV3 prolongs neutrophil lifespan by stabilizing the anti-apoptotic protein, myeloid cell leukemia-1 protein 20 , and generating molecules that can recruit neutrophils and other immune cells to promote in ammation and in ammatory damage.…”

“…Several viruses such as IAV, RSV, HCMV, and DV2 extend neutrophil survival through the PI3K and NF-κB pathways while others result in secretion of pro-survival factors or induce anti-apoptotic protein stabilization 26 . Mcl-1 is a crucial moderator of neutrophil survival and its deletion or accelerated turnover leads to accelerated apoptosis 20,45 . Mcl-1 protein levels are subject to rapid proteosomal degradation 46 and in ammatory agents stabilise this protein to prolong neutrophil survival 47 .…”

Two-faced Janus: the dual role of macrophages in atherosclerotic calcification

“… 151 , 152 Similarly, lipid exposure in murine bone marrow-derived macrophages could trigger multinucleated giant cell formation in culture, a phenotype that could be greatly exacerbated by myeloid Mcl-1 depletion in Ldlr −/− mice where a lipid accumulating, giant cell forming and apoptosis prone phenotype in macrophages was demonstrated. 153 Furthermore, hyperlipidaemia in Ldlr −/− mice, which is associated with increased plasma oxLDL levels, was seen to increase osteoclastogenesis potential in pre-osteoclasts ex vivo. 154 Cochain et al 48 reported a triggering receptor expressed on myeloid cells 2 (TREM2) high, OPN expressing macrophage subset, probably foam cells, in single-cell sequencing of CD45 + cells isolated from the atherosclerotic aorta of Ldlr −/− mice fed a western-type diet.…”