Oxidized low-density lipoprotein induces M2-type differentiation of macrophages to promote the protracted progression of atherosclerotic inflammation in high-fat diet-fed ApoE -/- mice

Abstract

In this study, the significance of oxidized low-density lipoprotein (ox-LDL) in promoting the progression of atherosclerosis was investigated by inducing the differentiation of macrophages into the M2 subtype within a high-fat diet-induced ApoE -/-mouse model. The study also evaluated the effects of β2-AR agonists and blockers on this process. Ox-LDL was found to have significantly promoted the differentiation of macrophages into the M2 type and induced related functional alterations. Furthermore, it activated the pyroptosis pathway and encouraged the release of lactate dehydrogenase. The administration of β2-AR agonists intensified these processes, while β2-AR blockers had the opposite effect. In animal experiments, the model group displayed elevated numbers of M2-type macrophages beneath the aortic root intima, an increased rate of plaque destruction, and the formation of atherosclerotic plaques compared to the control group. The SAL (Salbutamol) group exhibited even more severe plaque development than the model group. Conversely, the ICI (ICI118551) group demonstrated M2-type macrophage levels comparable to the control group, with a higher plaque destruction rate than controls but significantly lower than the model group, and no atherosclerotic plaques. These findings suggest that ox-LDL promoted the differentiation of recruited monocytes into M2-type macrophages, leading to a shift in the inflammatory response from M1 to M2 macrophages. This alteration resulted in the persistence of atherosclerotic inflammation, as M2-type macrophages were prone to cell membrane rupture (such as pyroptosis), contributing to the continuous recruitment of circulating monocytes and heightened inflammatory reactions within atherosclerotic plaques. Consequently, this process fueled the progression of atherosclerosis.

Inhibition of differentiation of monocyte-derived macrophages toward an M2-Like phenotype May Be a neglected mechanism of β-AR receptor blocker therapy for atherosclerosis

“…Considering that lipids persist within plaques without being removed, our research group concluded that a vicious cycle occurs during atherosclerosis progression involving recruitment and differentiation of M1-type macrophages into M2like phenotypes followed by phagocytosis and subsequent death processes. This cycle perpetuates itself by recruiting more M1-type macrophages for differentiation into M2-like phenotypes followed by phagocytosis and death (Zhang et al, 2023) (see Figure 2).…”

“…4.2 β-AR receptor blockers, via β2-AR, inhibit lipid-induced macrophage differentiation from M1-like phenotype to M2-like phenotype and inhibit atherosclerosis progression (Zhang et al, 2023) Our previous study demonstrated that β2-AR stimulators can enhance the effects of ox-LDL on macrophage function. However, metoprolol, propranolol (Smith and Teitler, 1999;Hoffmann et al, 2004;Baker, 2005) and ICI118551, which exhibit varying degrees of selectivity for β2-AR, can transduce signals through β2-AR and inhibit the effects of ox-LDL on macrophage function.…”

“…Cytological studies have revealed that lipids can induce macrophage differentiation towards an M2-like phenotype ( Sokolov et al, 2014 ; Seo et al, 2015 ; Pireaux et al, 2016 ; Lin et al, 2021 ; Zhang et al, 2023 ). Previous investigations have demonstrated that approximately 22% of subendothelial macrophages exhibit characteristics of “M2” or “selectively activated” macrophages after phagocytosis of lipids ( Taleb, 2016 ).…”

“…Our research group has proposed that this phenomenon may be attributed to the persistent phagocytosis of lipids by M2-like phenotype foam cells, which can activate the formation of NLRP3 inflammatory vesicles. This activation initiates the pyroptosis pathway and leads to the release of IL-18 and IL-1β from dying foam cells ( Lin et al, 2013 ; Zhang et al, 2023 ). The chemotactic effect of IL-1β on monocyte-derived macrophages is well-known in promoting atherosclerosis formation in coronary arteries, as its levels have been shown to correlate with disease severity ( Rajamäki et al, 2010 ; Mai and Liao, 2020 ).…”

“…Additionally, besides apoptosis, focal death associated with cell membrane rupture can occur in foam cells due to activation of specific death pathways such as pyroptosis. This process further promotes atherosclerosis progression ( Lin et al, 2013 ; Zhang et al, 2023 ). Furthermore, when foam cells undergo pyroptotic death, they trigger a pro-inflammatory response and contribute to atherosclerosis progression through cell membrane rupture and release of DAMPs.…”