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

Background: 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. methods: 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. results: 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. conclusions: 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. © 2015 zizzo and cohen; licensee biomed central.