Peroxisome proliferator-activated receptor alpha is an essential factor in enhanced macrophage immune function induced by angiotensin-converting enzyme

IF 21.8 1区 医学 Q1 IMMUNOLOGY
Suguru Saito, Duo-Yao Cao, Ellen A. Bernstein, Tomohiro Shibata, Anthony E. Jones, Amy Rios, Aoi O. Hoshi, Aleksandr B. Stotland, Erika E. Nishi, Jennifer E. Van Eyk, Ajit Divakaruni, Zakir Khan, Kenneth E. Bernstein
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Abstract

Increased expression of angiotensin-converting enzyme (ACE) by myeloid lineage cells strongly increases the immune activity of these cells, as observed in ACE10/10 mice, which exhibit a marked increase in antitumor and antibactericidal immunity. We report that peroxisome proliferator-activated receptor alpha (PPARα), a transcription factor that regulates genes critical for lipid metabolism, is a key molecule in the enhanced macrophage function induced by ACE. Here, we used a Cre–LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARα expression is selectively suppressed. These mice, termed A10-PPARα-Cre, have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages, resulting in reduced tumor antigen-specific CD8+ T-cell generation. Additionally, the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice, such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus (MRSA) infection. THP-1 cells expressing increased ACE (termed THP-1-ACE) constitute a human macrophage model with increased PPARα that shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA. RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance. In contrast, the in vivo administration of pemafibrate, a specific agonist of PPARα, to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%, respectively, but pemafibrate reduced tumors by 57.8% in ACE10/10 mice. With pemafibrate, the number of antitumor CD8+ T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice. We conclude that PPARα is important in the immune system of myeloid cells, including wild-type cells, and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.

Abstract Image

过氧化物酶体增殖物激活受体α是血管紧张素转换酶诱导巨噬细胞免疫功能增强的重要因素。
在ACE10/10小鼠中观察到,髓系细胞血管紧张素转换酶(ACE)表达的增加强烈地增加了这些细胞的免疫活性,其抗肿瘤和抗菌免疫能力显着增加。我们报道过氧化物酶体增殖激活受体α (PPARα)是一种调节脂质代谢关键基因的转录因子,是ACE诱导巨噬细胞功能增强的关键分子。在这里,我们使用Cre-LoxP方法和LysM-Cre创建了一个改良的ACE10/10小鼠系,其中巨噬细胞继续产生丰富的ACE,但单核细胞和巨噬细胞PPARα的表达被选择性抑制。这些小鼠被称为A10-PPARα-Cre,与Cre表达的ACE10/10小鼠相比,B16-F10肿瘤的生长明显增加。PPARα缺失会破坏表达ace的巨噬细胞的细胞因子产生和抗原呈递活性,导致肿瘤抗原特异性CD8+ t细胞生成减少。此外,在A10-PPARα-Cre小鼠中,ACE10/10小鼠典型的抗菌抗性升高明显降低,使得这些小鼠对耐甲氧西林金黄色葡萄球菌(MRSA)感染的抗性与WT小鼠相似。表达ACE增加的THP-1细胞(称为THP-1-ACE)构成了PPARα增加的人巨噬细胞模型,显示出对肿瘤细胞增强的细胞毒性和更好的吞噬和杀死MRSA。RNA沉默THP-1-ACE细胞中的PPARα可减少肿瘤细胞死亡和细菌吞噬和清除。相比之下,ppara α特异性激动剂pemafibrate在WT和a10 - ppara α- cre小鼠体内分别使B16-F10肿瘤生长减少24.5%和25.8%,而在ACE10/10小鼠中,pemafibrate使肿瘤生长减少57.8%。pembro颤动治疗后,A10-PPARα-Cre小鼠抗肿瘤CD8+ T细胞数量明显低于ACE10/10小鼠。我们得出结论,PPARα在骨髓细胞(包括野生型细胞)的免疫系统中是重要的,并且在ACE10/10小鼠中表达ace的巨噬细胞中其表达的增加对于小鼠和人类细胞中巨噬细胞的ace依赖性功能上调是必不可少的。
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来源期刊
CiteScore
31.20
自引率
1.20%
发文量
903
审稿时长
1 months
期刊介绍: Cellular & Molecular Immunology, a monthly journal from the Chinese Society of Immunology and the University of Science and Technology of China, serves as a comprehensive platform covering both basic immunology research and clinical applications. The journal publishes a variety of article types, including Articles, Review Articles, Mini Reviews, and Short Communications, focusing on diverse aspects of cellular and molecular immunology.
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