Saito Suguru, Cao DuoYao, Bernstein Ellen A, Jones Anthony E, Rios Amy, Hoshi Aoi O, Stotland Aleksandr B, Nishi Erika E, Shibata Tomohiro, Ahmed Faizan, Van Eyk Jennifer E, Divakaruni Ajit, Khan Zakir, Bernstein Kenneth E
Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Res Sq. 2024 Apr 22:rs.3.rs-4255086. doi: 10.21203/rs.3.rs-4255086/v1.
An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans.
血管紧张素转换酶（ACE）表达上调可增强髓系细胞的免疫活性，这是我们免疫系统中的一种自然功能调节机制。与野生型（WT）小鼠相比，巨噬细胞中ACE表达增加的ACE10/10小鼠表现出更强的抗肿瘤免疫力和杀菌作用，但其详细的分子机制尚未阐明。在本报告中，我们证明过氧化物酶体增殖物激活受体α（PPARα）是ACE诱导的巨噬细胞功能上调中的关键分子。PPARα是一种调节脂肪酸代谢相关基因表达的转录因子，在ACE过表达的巨噬细胞中其表达上调。为了确定PPARα在ACE过表达巨噬细胞增强免疫功能中的作用，我们基于ACE 10/10小鼠利用溶菌酶2（LysM）-Cre系统建立了髓系细胞选择性PPARα缺失的品系（命名为A10-PPARα-Cre）。有趣的是，A10-PPARα-Cre小鼠的B16-F10起源肿瘤比原始的ACE 10/10小鼠更大。PPARα缺失损害了ACE过表达巨噬细胞中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细胞活性降低。此外，A10-PPARα-Cre小鼠的杀菌作用也受损，在耐甲氧西林金黄色葡萄球菌（MRSA）感染中导致与WT小鼠相似的细菌定植。PPARα缺失下调了ACE过表达巨噬细胞的吞噬活性和细菌杀伤能力。此外，作为人类模型的THP-1-ACE衍生巨噬细胞，其PPARα表达上调，对B16-F10细胞的细胞毒性和对MRSA的杀伤能力增强。在THP-1-ACE细胞中，PPARα激动剂WY 14643进一步增强了这些活性，而拮抗剂GW6471则消除了这些活性。因此，PPARα是小鼠和人类中ACE依赖性巨噬细胞功能上调中不可或缺的分子。
