The PPAR-γ antagonist GW9662 elicits differentiation of M2c-like cells and upregulation of the MerTK/Gas6 axis: a key role for PPAR-γ in human macrophage polarization.
The PPAR-γ antagonist GW9662 elicits differentiation of M2c-like cells and upregulation of the MerTK/Gas6 axis: a key role for PPAR-γ in human macrophage polarization.
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PPAR-γ拮抗剂GW9662引起了M2C样细胞的分化和MERTK/GAS6轴的上调：PPAR-γ在人类巨噬细胞极化中的关键作用。
DOI：
10.1186/s12950-015-0081-4
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Cohen PL
中科院分区：
文献类型：
--
作者：
Zizzo G;Cohen PL
核受体PPAR-γ和LXR调节巨噬细胞脂质代谢和巨噬细胞介导的炎症。我们研究了这些分子对巨噬细胞交替激活的影响，特别关注“M2 c”抗炎细胞的分化。我们在M0、M1、M2 a或M2 c巨噬细胞分化条件下，在存在或不存在PPAR-γ和LXR配体的情况下培养人单核细胞。流式细胞术用于分析表型标志物的膜表达。通过ELISA测量基础和LPS刺激的可溶性介质的产生。通过将单核细胞/巨噬细胞与凋亡中性粒细胞共孵育进行胞饮试验。我们发现，使用PPAR-γ拮抗剂GW 9662抑制PPAR-γ，可促进M2 c样（CD 206 + CD 163 + CD 16+）细胞的分化和MerTK/Gas 6轴的上调。然而，分化中的巨噬细胞暴露于IFN-γ、GM-CSF或LPS（M1条件）阻碍了GW 9662对MerTK和Gas 6的诱导。当巨噬细胞用IL-4分化时（M2 a条件），添加GW 9662导致M2 a（CD 206 + CD 209 + CD 163 − MerTK−）向M2 c（CD 206高CD 209 − CD 163 + MerTK+）极化转变。相反，在地塞米松存在下（M2 c条件），PPAR-γ激动剂罗格列酮减弱CD 163和MerTK上调。LXR激动剂T0901317独立于M2 c极化诱导MerTK;实际上，CD 206、CD 163和CD 16下调。GW 9662分化的M2 c样细胞分泌高水平的Gas 6和低量的TNF-α和IL-10，模拟地塞米松的体外作用。然而，与常规的M2 c细胞不同，GW 9662分化的细胞不显示增强的促红细胞生成能力。我们的研究结果为PPAR-γ和LXR受体在人巨噬细胞活化中的作用提供了新的见解，并揭示了调节MerTK表达的不同模式的存在。出乎意料的是，PPAR-γ似乎负控制M2 c样抗炎巨噬细胞的离散子集的扩增。
The nuclear receptors PPAR-γ and LXRs regulate macrophage lipid metabolism and macrophage mediated inflammation. We examined the influence of these molecules on macrophage alternative activation, with particular focus on differentiation of “M2c” anti-inflammatory cells. We cultured human monocytes in M0, M1, M2a or M2c macrophage differentiating conditions, in the presence or absence of PPAR-γ and LXR ligands. Flow cytometry was used to analyze membrane expression of phenotypic markers. Basal and LPS-stimulated production of soluble mediators was measured by ELISA. Efferocytosis assays were performed by coincubating monocytes/macrophages with apoptotic neutrophils. We found that PPAR-γ inhibition, using the PPAR-γ antagonist GW9662, elicits differentiation of M2c-like (CD206+ CD163+ CD16+) cells and upregulation of the MerTK/Gas6 axis. Exposure of differentiating macrophages to IFN-γ, GM-CSF or LPS (M1 conditions), however, hampers GW9662 induction of MerTK and Gas6. When macrophages are differentiated with IL-4 (M2a conditions), addition of GW9662 results into an M2a (CD206+ CD209+ CD163− MerTK−) to M2c (CD206high CD209− CD163+ MerTK+) polarization shift. Conversely, in the presence of dexamethasone (M2c conditions), the PPAR-γ agonist rosiglitazone attenuates CD163 and MerTK upregulation. The LXR agonist T0901317 induces MerTK independently of M2c polarization; indeed, CD206, CD163 and CD16 are downregulated. GW9662-differentiated M2c-like cells secrete high levels of Gas6 and low amounts of TNF-α and IL-10, mimicking dexamethasone effects in vitro. However, unlike conventional M2c cells, GW9662-differentiated cells do not show enhanced efferocytic ability. Our results provide new insights into the role of PPAR-γ and LXR receptors in human macrophage activation and reveal the existence of different patterns regulating MerTK expression. Unexpectedly, PPAR-γ appears to negatively control the expansion of a discrete subset of M2c-like anti-inflammatory macrophages.
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作者：
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