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Nlrp3, Csf3, and Edn1 in Macrophage Response to Saturated Fatty Acids and Modified Low-Density Lipoprotein

Korean Circulation Journal 2021년 51권 1호 p.68 ~ 80
육하린, Kim Mi-So, 이찬주, 오재원, 박성하, 강석민, 김정호, Ann Soo-Jin, 이상학,
소속 상세정보
육하린 ( Youk Ha-Rin ) - Yonsei University Graduate School Graduate Program of Science for Aging
 ( Kim Mi-So ) - Yonsei University Graduate School Graduate Program of Science for Aging
이찬주 ( Lee Chan-Joo ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine
오재원 ( Oh Jae-Won ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine
박성하 ( Park Sung-Ha ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine
강석민 ( Kang Seok-Min ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine
김정호 ( Kim Jeong-Ho ) - Yonsei University College of Medicine Department of Laboratory Medicine
 ( Ann Soo-Jin ) - Yonsei University Graduate School Graduate Program of Science for Aging
이상학 ( Lee Sang-Hak ) - Yonsei University College of Medicine Severance Hospital Department of Internal Medicine

Abstract


Background and Objectives: The relationship between metabolic stress, inflammation, and cardiovascular disease is being studied steadily. The aim of this study was to evaluate the effect of palmitate (PA) and minimally modified low-density lipoprotein (mmLDL) on macrophages and to identify the associated pathways.

Methods: J774 macrophages were incubated with PA or mmLDL and lipopolysaccharide (LPS). Secretion of inflammatory chemokines and the expression of corresponding genes were determined. The phosphorylation of extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase was also assessed. RNA sequencing of macrophages was performed to identify the genes regulated by PA or mmLDL. Some of the genes regulated by the 2 agents were validated by knocking down the cells using small interfering RNA.

Results: PA or mmLDL promoted the secretion of interleukin (IL)-6 and IL-1β in LPS-stimulated macrophages, and this was accompanied by higher phosphorylation of ERK. RNA sequencing revealed dozens of genes that were regulated in this process, such as Csf3 and Edn1, which were affected by PA and mmLDL, respectively. These agents also increased Nlrp3 expression. The effect of Csf3 or Edn1 silencing on inflammation was modest, whereas toll-like receptor (TLR) 4 inhibition reduced a large proportion of macrophage activation.

Conclusions: We demonstrated that the proinflammatory milieu with high levels of PA or mmLDL promoted macrophage activation and the expression of associated genes such as Nlrp3, Csf3, and Edn1. Although the TLR4 pathway appeared to be most relevant, additional role of other genes in this process provided insights regarding the potential targets for intervention.

키워드

Atherosclerosis; Metabolic syndrome; Immunity; Obesity

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