Treatment in vitro with PPARα and PPARγ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice
Treatment in vitro with PPARα and PPARγ ligands drives M1-to-M2 polarization of macrophages from T. cruzi-infected mice
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DOI：
10.1016/j.bbadis.2014.12.019
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发表时间：
2015-05-01
影响因子：
6.2
通讯作者：
Goren, Nora B.
中科院分区：
文献类型：
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作者：
Penas, Federico;Mirkin, Gerardo A.;Goren, Nora B.
克氏锥虫 (Tiypanosoma cruzi) 是恰加斯病的病原体，可诱导持续的炎症反应。巨噬细胞是参与清除感染的一线细胞表型。寄生虫摄取后，这些细胞会增加 NO、TNF-α、IL-β 和 IL-6 等炎症介质，从而杀死寄生虫。尽管是所希望的，但炎症反应的持续和加剧可能会导致组织损伤。过氧化物酶体增殖物激活受体（PPAR）是配体依赖性核转录因子，除了调节脂质和碳水化合物代谢外，还具有显着的抗炎作用。这是通过受体与其配体的相互作用介导的。 PPARγ，PPAR亚型之一，在不同的代谢紊乱和感染模型中涉及从M1（经典激活表型）到M2（替代激活表型）的巨噬细胞极化。在这项研究中，我们首次证明，除了 PPAR γ 之外，PPAR α 也参与从克氏锥虫感染的小鼠中分离出的巨噬细胞的体外极化。 NOS2 和促炎细胞因子表达的减少以及精氨酸酶 I、Ym1、甘露糖受体和 TGF-β 等 M2 标记物的增加证明了极化。此外，巨噬细胞的吞噬活性显着增强，导致寄生虫负荷增加。我们认为，两种 PPAR 对炎症反应的调节可能至少部分归因于炎症巨噬细胞特征的变化。 PPAR 激动剂作为恰加斯病过程中明显炎症反应调节剂的潜在用途值得进一步研究。 (C) 2015 Elsevier B.V. 保留所有权利。
Tiypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-alpha, IL-beta and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPAR gamma, one of the PPAR isoforms, has been implicated in macrophage polarization from Ml, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPAR gamma, PPAR alpha is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-beta. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation. (C) 2015 Elsevier B.V. All rights reserved.