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Interleukin-1β promotes an atheroprotective distribution of smooth muscle cells and macrophages in late stage murine atherosclerotic lesion

ABSTRACT: Despite decades of research, our understanding of processes controlling the stability of late-stage atherosclerotic plaques remains poor. However, a prevailing hypothesis is that reducing inflammation may improve plaque stability. Indeed, the potent inflammatory cytokine, interleukin-1β (IL-1β), has been shown to be a key driver of atherosclerosis development. Importantly, the CANTOS Trial recently demonstrated that administration of an anti-IL-1β antibody to high-risk post-myocardial infarction (MI) patients reduced the incidence of recurrent nonfatal MI, but did not reduce the incidence of cardiovascular death or stroke. As such, although the CANTOS trial results providing exciting evidence that targeting inflammation can have clinical benefit for treating advanced atherosclerosis, extensive further investigation is needed to better understand the mechanisms by which IL-1β inhibition impacts established lesions. Therefore, we performed intervention studies on smooth muscle cell (SMC) lineage tracing mice with advanced atherosclerosis using anti-IL- 1 or IgG control antibodies. Surprisingly, we found no effect on lesion size but a profound shift in the composition of the fibrous cap characterized by reduced collagen and SMC content but an increase in macrophage number, which was primarily driven by opposite effects on the proliferation of these respective cell types. By generating SMC-specific and macrophage-selective Il1r1 KO Apoe -/- mice, we found that SMC-specific Il1r1 KO resulted in a ~60% reduction in lesion size and lesions that were nearly devoid of YFP + SMC whereas, myeloid-selective loss of IL1R1 had no effect on lesion size, or cell composition. This suggests that SMC are a primary cell type responding to IL-1β in atherosclerosis and that IL1 signaling in SMC is critical for their investment and retention within the fibrous cap. In addition, we found that inhibition of IL-1β promoted an expansion of the M2 macrophage population within the fibrous cap, and that these effects may be due in part to elevated levels of IL4. Taken together, results show that IL-1β can promote beneficial changes in late-stage murine atherosclerosis by promoting maintenance of a SMC/collagen-rich fibrous cap. Moreover, studies identify critical cell types and pathways that need to be considered when attempting to develop safer and more effective anti-inflammatory therapies for widespread treatment of atherosclerotic disease, including in moderate or low risk patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE111535 | GEO | 2018/07/12

REPOSITORIES: GEO

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Project description:Aryl-hydrocarbon receptor protects against endochondral ossification of modulated smooth muscle cells in atherosclerosis Introduction: Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC. Methods: We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracing Ahr knockout mouse model of atherosclerosis to better understand the role of AHR in vascular disease. Results: Genomic studies coupled with functional assays in cultured HCASMC revealed that AHR modulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that the Ahr pathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such as Col2a1 and Alpl, which localized to the lesion neointima. These cells, which we term chondromyocytes (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in the Ahr knockout compared to wild-type mice. We propose that AHR is likely protective based on these data and inference from human genetic analyses. Conclusion: Overall, we conclude that AHR promotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.

Project description:Cardiovascular disease is the leading cause of death in developed countries and there is compelling evidence that the majority of these fatalities are secondary to rupture of unstable atherosclerotic plaques. However, the mechanisms that control plaque stability are poorly understood, although it is widely believed that plaques having a decreased ratio of cells positive for smooth muscle cell (SMC) markers such as ACTA2 relative to macrophage markers are more likely to rupture. Herein we employMyh11-CreERT2 ROSA floxed STOP eYFP Apoe-/- mice to trace SMC lineage and show that traditional methods for detecting SMCs based on immunostaining for SMC markers like ACTA2 are unable to detect 82% of SMC-derived cells within advanced atherosclerotic lesions. Moreover, we show that these SMC-derived cells within advanced lesions exhibit multiple phenotypes including activation of multiple markers of macrophages, mesenchymal stem cells (MSC), and myofibroblasts (MF). Importantly, we show that SMC-derived macrophage like cells are phagocytic based on electron microscope YFP immunolabeling. In addition, results of single cell epigenetic assays developed in our lab shows that nearly 20% of macrophage-like cells within human lesions are of SMC not myeloid origin. These phenotypic transitions appear to be critical in lesion pathogenesis, in that we show that SMC-specific conditional knockout (KO) of the pluripotency factor, Krüppel-like factor 4 (KLF4), resulted in marked reductions in lesion size, increases in multiple indices of plaque stability, and reduced numbers of SMC-derived MSC- and macrophage-like cells. Finally, we show that cholesterol loading of cultured SMC is associated with activation of multiple markers of macrophages and MSC, secretion of pro-inflammatory cytokines, and increased phagocytosis, all of which are Klf4 dependent. Taken together, results indicate that the contribution of SMCs within atherosclerotic plaques has been greatly underestimated, and that loss of Klf4 within SMC result in major changes in SMC phenotype and function that play a major role in lesion pathogenesis. Examination of KLF4 transcription factor in an atherosclerosis setting

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Interleukin-1β promotes an atheroprotective distribution of smooth muscle cells and macrophages in late stage murine atherosclerotic lesion

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