期刊
JOURNAL OF INFLAMMATION-LONDON
卷 12, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12950-015-0081-4
关键词
Macrophages; M2; Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma); Liver X Receptor (LXR); Mer receptor Tyrosine Kinase (MerTK); Gas6; CD163
类别
资金
- National Institute of Allergy and Infectious Diseases (NIAID) [5U19AI082726]
- Judith Shockman Memorial Fund
Background: The nuclear receptors PPAR-gamma 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. Methods: We cultured human monocytes in M0, M1, M2a or M2c macrophage differentiating conditions, in the presence or absence of PPAR-gamma 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. Results: We found that PPAR-gamma inhibition, using the PPAR-gamma antagonist GW9662, elicits differentiation of M2c-like (CD206(+) CD163(+) CD16(+)) cells and upregulation of the MerTK/Gas6 axis. Exposure of differentiating macrophages to IFN-gamma, 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 (CD206(high) CD209(-) CD163(+) MerTK(+)) polarization shift. Conversely, in the presence of dexamethasone (M2c conditions), the PPAR-gamma 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-alpha and IL-10, mimicking dexamethasone effects in vitro. However, unlike conventional M2c cells, GW9662-differentiated cells do not show enhanced efferocytic ability. Conclusions: Our results provide new insights into the role of PPAR-gamma and LXR receptors in human macrophage activation and reveal the existence of different patterns regulating MerTK expression. Unexpectedly, PPAR-gamma appears to negatively control the expansion of a discrete subset of M2c-like anti-inflammatory macrophages.
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