Rapamycin and FTY720 Alleviate Atherosclerosis by Cross Talk of Macrophage Polarization and Autophagy

Abstract

Foam cell formation and macrophage polarization are involved in the pathologic development of atherosclerosis, one of the most important human diseases affecting large and medium artery walls. This study was designed to assess the effects of rapamycin and FTY720 (fingolimod) on macrophages and foam cells. Mouse peritoneal macrophages were collected and treated with rapamycin and FTY720 to study autophagy, polarization, and lipid accumulation. Next, foam cells were formed by oxidizing low-density lipoprotein to observe changes in lipid accumulation, autophagy, and polarization in rapamycin-treated or FTY720-treated foam cells. Lastly, foam cells that had been treated with rapamycin and FTY720 were evaluated for sphingosine 1-phosphate receptor (S1prs) expression. Autophagy microtubule-associated protein 1 light chain 3- (LC3-) II was increased, and classically activated macrophage phenotype markers interleukin- (IL-) 6, cyclooxygenase-2 (COX2), and inducible nitric oxide synthase (iNOS) were increased, whereas alternatively activated macrophage phenotype markers transforming growth factor- (TGF-) β, arginase 1 (Arg1), and mannose receptor C-type 1 (Mrc1) were decreased by rapamycin in peritoneal macrophages. LC3-II was also obviously enhanced, though polarization markers were unchanged in rapamycin-treated foam cells. Moreover, lipid accumulation was inhibited in rapamycin-treated macrophage cells but was unchanged in rapamycin-treated foam cells. For FTY720, LC3-II did not change, whereas TGF-β, Arg1 and Mrc1 were augmented, and IL-6 was suppressed in macrophages. However, LC3-II was increased, and TGF-β, ARG1 and MRC1 were strikingly augmented, whereas IL-6, COX2 and iNOS could be suppressed in foam cells. Furthermore, lipid accumulation was alleviated in FTY720-treated foam cells. Additionally, S1pr1 was markedly decreased in foam cells (P < .05); S1pr2, S1pr3, S1pr4 and S1pr5 were unchanged in rapamycin-treated foam cells. In FTY720-treated foam cells, S1pr3 and S1pr4 were decreased, and S1pr1, S1pr2 and S1pr5 were unchanged. Therefore, we deduced that rapamycin stimulated classically activated macrophages and supressed early atherosclerosis. Rapamycin may also stabilize artery plaques by preventing apoptosis and S1PR1 in advanced atherosclerosis. FTY720 allowed transformation of foam cells into alternatively activated macrophages through the autophagy pathway to alleviate advanced atherosclerosis.

FTY720 reactivates cryptococcal granulomas in mice through S1P receptor 3 on macrophages

“…It has also been suggested that S1P promotes M1 polarization in macrophages through S1PR3 (50,51) and that FTY720 blocks this polarization and may instead promote M2 polarization (50,52,53). Indeed, we observed that FTY720 treatment induces M2 polarization, which is confined within the fibrotic layer of the granulomas.…”

Therapeutic Potential of SphK1 Inhibitors Based on Abnormal Expression of SphK1 in Inflammatory Immune Related-Diseases

“…Macrophage apoptosis is considered to be a key step in the formation of unstable plaque in atherosclerotic. Macrophage apoptosis is inhibited by FTY-720 and PF-543 through cross-talk of macrophage polarization and autophagy and S1P signal, which helps to prevent the formation of unstable plaque ( Sun et al, 2018 ; Zhu et al, 2020 ). Furthermore, activation of SphK1 is essential in vascular inflammation mediated by inflammatory cytokines such as TNF-α.…”

Danlou Tablets Inhibit Atherosclerosis in Apolipoprotein E-Deficient Mice by Inducing Macrophage Autophagy: The Role of the PI3K-Akt-mTOR Pathway

“…Our results showed that DLTs could obviously alleviate macrophage transformation into foam cells (MFI), accumulation of lipid droplets (oil red O staining) and infiltration (CD68) in arterial tissues. The role of autophagy in macrophage lipid metabolism has been highlighted by many researchers (Sun, Fan et al, 2018;Cao, Jia et al, 2019;Zhou, Ren et al, 2019). MD Khurshidul Zahid et al found that enhancing autophagy could drive cholesterol efflux and inhibit macrophagic foam cell formation in RAW264.7 cells (Zahid, Rogowski et al, 2020).…”

“…The role of autophagy in macrophage lipid metabolism has been highlighted by many researchers ( Sun, Fan et al, 2018 ; Cao, Jia et al, 2019 ; Zhou, Ren et al, 2019 ). MD Khurshidul Zahid et al found that enhancing autophagy could drive cholesterol efflux and inhibit macrophagic foam cell formation in RAW264.7 cells ( Zahid, Rogowski et al, 2020 ).…”