Interleukin 6-regulated macrophage polarization controls atherosclerosis-associated vascular intimal hyperplasia

Abstract

Vascular intimal hyperplasia (VIH) is an important stage of atherosclerosis (AS), in which macrophages not only play a critical role in local inflammation, but also transform into foam cells to participate into plaque formation, where they appear to be heterogeneous. Recently, it was shown that CD11c+ macrophages were more associated with active plaque progression. However, the molecular regulation of phenotypic changes of plaque macrophages during VIH has not been clarified and thus addressed in the current study. Since CD11c- cells were M2a-polarized anti-inflammatory macrophages, while CD11c+ cells were M1/M2b-polarized pro-inflammatory macrophages, we used bioinformatics tools to analyze the CD11c+ versus CD11c- plaque macrophages, aiming to detect the differential genes associated with M1/M2 macrophage polarization. We obtained 122 differential genes that were significantly altered in CD11c+ versus CD11c- plaque macrophages, regardless of CD11b expression. Next, hub genes were predicted in these 122 genes, from which we detected 3 candidates, interleukin 6 (Il6), Decorin (Dcn) and Tissue inhibitor matrix metalloproteinase 1 (Timp1). The effects of these 3 genes on CD11c expression as well as on the macrophage polarization were assessed in vitro, showing that only expression of Il6, but not expression of Dcn or Timp1, induced M1/M2b-like polarization in M2a macrophages. Moreover, only suppression of Il6, but not suppression of either of Dcn or Timp1, induced M2a-like polarization in M1/M2b macrophages. Furthermore, pharmaceutical suppression of Il6 attenuated VIH formation and progression of AS in a mouse model that co-applied apolipoprotein E-knockout and high-fat diet. Together, our data suggest that formation of VIH can be controlled through modulating macrophage polarization, as a promising therapeutic approach for prevent AS.

Vertical Sleeve Gastrectomy Offers Protection against Disturbed Flow-Induced Atherosclerosis in High-Fat Diet-Fed Mice

“…IL-6, which is synthesized and released by macrophages, smooth muscle cells, and endothelial cells, plays a pivotal role in the early stages of atherosclerotic plaque formation. IL-6 can be resident or trapped in arterial walls, playing an important role in the phenotypic determination of plaque macrophages, polarization and shaping of macrophages, and development of vascular intimal hyperplasia and atherosclerosis [ 29 ]. Although we did not examine macrophage composition, studies have indicated that M2 macrophages are polarized after SG, which may be relevant to the results of vascular intimal hyperplasia and inflammation [ 30 , 31 ].…”

Transcriptional data analysis reveals the association between infantile hemangiomas and venous malformations

“…IL6 (interleukin 6) encodes a cytokine that functions in many autoimmune diseases or infections. It is reported that IL6 can regulate macrophage polarization controls atherosclerosis associated vascular intimal hyperplasia ( Chen et al, 2022 ). Dritsoula et al (2022) demonstrated that IL-6, through STAT3 phosphorylation, activates LRG1 transcription resulting in vascular destabilization.…”

Phytochemical Composition and Antioxidant and Anti-Inflammatory Activities of Humboldtia sanjappae Sasidh. & Sujanapal, an Endemic Medicinal Plant to the Western Ghats

“…Together with IL-1β, IL-6 was also found to significantly influence the inflammation in macrophages [87,88]. IL-6 has a major role in the innate immune defense systems [89]; however, the same molecule is associated with the progression of various diseases [90,91].…”