IFN‐γ aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin‐dependent liver X receptor‐α degradation

Abstract

Neointimal hyperplasia is the main cause of restenosis after percutaneous coronary interventions (PCIs). Both IFN-γ and macrophages play nonredundant roles in the pathogenesis of vascular intimal hyperplasia; however, the underlying mechanisms remain elusive and must be further investigated. In mouse peritoneal macrophages, IFN-γ significantly accelerated degradation and up-regulated polyubiquitination of liver X receptor (LXR)-α. Signal transducer and activator of transcription 1 (STAT1) inhibitor, fludarabine, and PIAS1 knockdown reduced ubiquitination and increased the expression of LXR-α in IFN-γ-treated macrophages. IFN-γ also increased the expression of endoplasmic reticulum (ER) stress-related proteins, including p-PERK, p-eIIF2α, and CCAAT-enhancer-binding protein homologous protein (CHOP), as well as apoptosis of macrophages. Treatment with ER stress inhibitor, 4-phenylbutyric acid (4-PBA), and LXR agonist, T0901317 (T0), alleviated IFN-γ-induced apoptosis in macrophages. Neointimal hyperplasia was significant after carotid ligation for 4 wk in ApoE mice. IFN-γ mAb, T0, and 4-PBA treatment not only significantly attenuated neointimal hyperplasia but also decreased CD68TUNEL double-positive macrophages in the hyperplastic neointima. Moreover, after 4-PBA or T0 administration, the number of CD68p-eIIF2α and CD68CHOP double-positive cells in neointimal was also apparently decreased. Taken together, these results defined an unexpected role of IFN-γ and LXR-α in the development of neointimal hyperplasia. The PIAS1/STAT1-dependent LXR-α degradation induced by IFN-γ promoted ER stress and apoptosis in macrophages, which leads to aggravated neointimal hyperplasia. LXR agonist efficiently improved neointimal hyperplasia, which may be a promising new strategy to ameliorate restenosis and vascular remodeling after PCI.-Zhao, Q., Zhou, D., You, H., Lou, B., Zhang, Y., Tian, Y., Guo, N., Chen, X., Liu, Y., Wu, Y., Yuan, Z., Zhou, J. IFN-γ aggravates neointimal hyperplasia by inducing endoplasmic reticulum stress and apoptosis in macrophages by promoting ubiquitin-dependent liver X receptor-α degradation.

Endoplasmic Reticulum Stress Affects Cholesterol Homeostasis by Inhibiting LXRα Expression in Hepatocytes and Macrophages

“…For example, Ge et al demonstrated that betaine ameliorated hepatic lipid accumulation and inflammation through restoring LXRα and PPARα expression and alleviating ER stress in fructose-fed rats—an experiment which indicated that only LXRα participated in ER stress [ 24 ]. Furthermore, Zhao et al confirmed that LXRα degradation is a key factor that induces ER stress stimulated by IFN-γ depending on the PIAS1/STAT1 pathway in macrophages [ 25 ]. However, the detailed mechanism is not fully clear.…”

Endoplasmic Reticulum Stress in Macrophages: The Vicious Circle of Lipid Accumulation and Pro-Inflammatory Response

“…Inflammatory response can enhance apoptosis in atherosclerotic lesion macrophages. It was shown that IFN-γ could significantly accelerate STAT1 (signal transducer and activator of transcription protein 1)-dependent degradation of the transcription factor LXRα (liver X receptor α), which can regulate cholesterol efflux by increasing the expression of ABCA1 and ABCG1 under abundance of cellular cholesterol via activation of its polyubiquitination [ 59 ], and upregulate the expression of PERK, eIIF2α, and CHOP proteins, thus contributing to ER stress and enhancing apoptotic processes [ 60 ]. TNFα might also promote ER stress-depended apoptosis in macrophages via activation of UPR pathways [ 61 ].…”

MicroRNA sequences modulating inflammation and lipid accumulation in macrophage “foam” cells: Implications for atherosclerosis

“…Pathway-specific responses occur: LXR activation inhibits NF-κB dependent induction of pro-inflammatory genes in response to LPS and responses triggered by TLR4 and TNF-α but exerts minimal impact on the pathway mediated by TLR3[ 86 - 88 ]. LXRs also regulate apoptosis and enhance survival of macrophages within lesions, while IFN-γ promotes neointimal hyperplasia and macrophage apoptosis by promoting ubiquitin-dependent LXR degradation[ 101 , 102 ].…”