The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.
The Activin A-Peroxisome Proliferator-Activated Receptor Gamma Axis Contributes to the Transcriptome of GM-CSF-Conditioned Human Macrophages.
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DOI：
10.3389/fimmu.2018.00031
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发表时间：
2018
影响因子：
7.3
通讯作者：
Corbí AL
中科院分区：
文献类型：
--
作者：
Nieto C;Bragado R;Municio C;Sierra-Filardi E;Alonso B;Escribese MM;Domínguez-Andrés J;Ardavín C;Castrillo A;Vega MA;Puig-Kröger A;Corbí AL
GM-CSF促进肺泡巨噬细胞（A-MMPs）的功能成熟，其分化依赖于过氧化物酶体增殖物激活受体γ（PPARγ）转录因子。事实上，阻断GM-CSF启动的信号传导或缺失PPARγ编码基因PPARG会导致功能缺陷的A-Mc和肺泡蛋白沉积症的发生。在体外，在GM-CSF存在下产生的巨噬细胞显示出有效的促炎性、免疫原性和肿瘤生长限制活性。由于GM-CSF上调了PPARγ的表达，我们假设PPARγ可能对人GM-CSF条件巨噬细胞的基因特征和功能谱有贡献。为了验证这一假设，在存在GM-CSF [促炎性GM-CSF条件化人单核细胞源性巨噬细胞（GM-CSF）]或M-CSF（抗炎性M-CSF）的情况下生成的人单核细胞源性巨噬细胞中以及在离体分离的人A-CSF中评估了PPARγ表达和活性。结果表明，GM-Mc中的PPARγ表达高于M-Mc，且在GM-Mc中的表达主要依赖激活素A。配体诱导的PPARγ活化也导致GM-Mc和M-Mc中不同的转录和功能结果。此外，在不存在外源激活配体的情况下，PPARγ敲低显着改变了GM-MØ转录组，导致促炎基因的全面上调，并显着调节参与细胞增殖和迁移的基因的表达。在离体分离的人A-Mc中观察到类似的效应，其中PPARγ沉默导致编码生长因子和趋化因子的基因的表达增强以及细胞表面病原体受体的下调。因此，在不存在外源性活化配体的情况下，PPARγ塑造了GM-CSF依赖性人巨噬细胞（体外衍生的GM-McAb和离体分离的A-McAb）的转录组，其表达主要受激活素A调节。这些结果表明，激活素A通过增强PPARγ表达，帮助巨噬细胞从促炎性极化状态转换为抗炎性极化状态，从而有助于限制组织损伤并恢复稳态。
GM-CSF promotes the functional maturation of lung alveolar macrophages (A-MØ), whose differentiation is dependent on the peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor. In fact, blockade of GM-CSF-initiated signaling or deletion of the PPARγ-encoding gene PPARG leads to functionally defective A-MØ and the onset of pulmonary alveolar proteinosis. In vitro, macrophages generated in the presence of GM-CSF display potent proinflammatory, immunogenic and tumor growth-limiting activities. Since GM-CSF upregulates PPARγ expression, we hypothesized that PPARγ might contribute to the gene signature and functional profile of human GM-CSF-conditioned macrophages. To verify this hypothesis, PPARγ expression and activity was assessed in human monocyte-derived macrophages generated in the presence of GM-CSF [proinflammatory GM-CSF-conditioned human monocyte-derived macrophages (GM-MØ)] or M-CSF (anti-inflammatory M-MØ), as well as in ex vivo isolated human A-MØ. GM-MØ showed higher PPARγ expression than M-MØ, and the expression of PPARγ in GM-MØ was found to largely depend on activin A. Ligand-induced activation of PPARγ also resulted in distinct transcriptional and functional outcomes in GM-MØ and M-MØ. Moreover, and in the absence of exogenous activating ligands, PPARγ knockdown significantly altered the GM-MØ transcriptome, causing a global upregulation of proinflammatory genes and significantly modulating the expression of genes involved in cell proliferation and migration. Similar effects were observed in ex vivo isolated human A-MØ, where PPARγ silencing led to enhanced expression of genes coding for growth factors and chemokines and downregulation of cell surface pathogen receptors. Therefore, PPARγ shapes the transcriptome of GM-CSF-dependent human macrophages (in vitro derived GM-MØ and ex vivo isolated A-MØ) in the absence of exogenous activating ligands, and its expression is primarily regulated by activin A. These results suggest that activin A, through enhancement of PPARγ expression, help macrophages to switch from a proinflammatory to an anti-inflammatory polarization state, thus contributing to limit tissue damage and restore homeostasis.
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影响因子：
4.8
作者：
Dasu, Mohan R.;Park, Samuel;Jialal, Ishwarlal
通讯作者：
Jialal, Ishwarlal
DOI：
10.4049/jimmunol.181.1.235
发表时间：
2008-07-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Bonfield TL;Thomassen MJ;Farver CF;Abraham S;Koloze MT;Zhang X;Mosser DM;Culver DA
通讯作者：
Culver DA
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1165/ajrcmb.24.4.4008
发表时间：
2001-04-01
影响因子：
6.4
作者：
Ferrari-Lacraz, S;Nicod, LP;Dayer, JM
通讯作者：
Dayer, JM
影响因子：
29
作者：
Bouhlel, M. Amine;Derudas, Bruno;Chinetti-Gbaguidi, Giulia
通讯作者：
Chinetti-Gbaguidi, Giulia