Kim Gun-Dong, Ng Hang Pong, Chan E Ricky, Mahabeleshwar Ganapati H
Department of Pathology, Case Western Reserve University, Cleveland, Ohio.
Institute for Computational Biology, Case Western Reserve University, Cleveland, Ohio.
Am J Pathol. 2021 Jun;191(6):1118-1134. doi: 10.1016/j.ajpath.2021.03.008. Epub 2021 Mar 19.
Macrophages play crucial and diverse roles in the pathogenesis of inflammatory vascular diseases. Macrophages are the principal innate immune cells recruited to arterial walls to govern vascular homeostasis by modulating the proliferation of vascular smooth muscle cells, the reorganization of extracellular matrix components, the elimination of dead cells, and the restoration of normal blood flow. However, chronic sterile inflammation within the arterial walls draws inflammatory macrophages into intimal/neointimal regions that may contribute to disease pathogenesis. In this context, the accumulation and aberrant activation of macrophages in the neointimal regions govern the progression of inflammatory arterial wall diseases. Herein, we report that myeloid-hypoxia-inducible factor-1α (HIF1α) deficiency attenuates vascular smooth muscle cells and macrophage abundance in stenotic arteries and abrogates carotid neointima formation in vivo. The integrated transcriptomics, Gene Set Enrichment Analysis, metabolomics, and target gene evaluation showed that HIF1α represses oxidative phosphorylation, tricarboxylic acid cycle, fatty acid metabolism, and c-MYC signaling pathways while promoting inflammatory, glycolytic, hypoxia response gene expression in stenotic artery macrophages. At the molecular level, proinflammatory agents utilized STAT3 signaling pathways to elevate HIF1α expression in macrophages. Collectively, this study uncovers that macrophage-HIF1α deficiency restrains the pathogenesis of carotid artery stenosis by rewiring inflammatory and metabolic signaling pathways in macrophages.
巨噬细胞在炎症性血管疾病的发病机制中发挥着关键且多样的作用。巨噬细胞是被招募到动脉壁的主要固有免疫细胞，通过调节血管平滑肌细胞的增殖、细胞外基质成分的重组、死细胞的清除以及正常血流的恢复来维持血管稳态。然而，动脉壁内的慢性无菌性炎症会将炎性巨噬细胞吸引到内膜/新生内膜区域，这可能有助于疾病的发病机制。在这种情况下，新生内膜区域巨噬细胞的积累和异常激活决定了炎症性动脉壁疾病的进展。在此，我们报告髓系缺氧诱导因子-1α（HIF1α）缺乏会减弱狭窄动脉中血管平滑肌细胞和巨噬细胞的丰度，并在体内消除颈动脉新生内膜的形成。综合转录组学、基因集富集分析、代谢组学和靶基因评估表明，HIF1α在狭窄动脉巨噬细胞中抑制氧化磷酸化、三羧酸循环、脂肪酸代谢和c-MYC信号通路，同时促进炎症、糖酵解、缺氧反应基因的表达。在分子水平上，促炎剂利用STAT3信号通路提高巨噬细胞中HIF1α的表达。总的来说，这项研究揭示了巨噬细胞-HIF1α缺乏通过重新连接巨噬细胞中的炎症和代谢信号通路来抑制颈动脉狭窄的发病机制。
