title: Rosiglitazone-induced CD36 up-regulation resolves inflammation by PPARγ and 5-LO-dependent pathways.
abstract: PPARγ-achieved neuroprotection in experimental stroke has been explained by the inhibition of inflammatory genes, an action in which 5-LO, Alox5, is involved. In addition, PPARγ is known to promote the expression of CD36, a scavenger receptor that binds lipoproteins and mediates bacterial recognition and also phagocytosis. As phagocytic clearance of neutrophils is a requisite for resolution of the inflammatory response, PPARγ-induced CD36 expression might help to limit inflammatory tissue injury in stroke, an effect in which 5-LO might also be involved. Homogenates, sections, and cellular suspensions were prepared from brains of WT and Alox5(-/-) mice exposed to distal pMCAO. BMMs were obtained from Lys-M Cre(+) PPARγ(f/f) and Lys-M Cre(-) PPARγ(f/f) mice. Stereological counting of double-immunofluorescence-labeled brain sections and FACS analysis of cell suspensions was performed. In vivo and in vitro phagocytosis of neutrophils by microglia/macrophages was analyzed. PPARγ activation with RSG induced CD36 expression in resident microglia. This process was mediated by the 5-LO gene, which is induced in neurons by PPARγ activation and at least by one of its products--LXA4--which induced CD36 independently of PPARγ. Moreover, CD36 expression helped resolution of inflammation through phagocytosis, concomitantly to neuroprotection. Based on these findings, in addition to a direct modulation by PPARγ, we propose in brain a paracrine model by which products generated by neuronal 5-LO, such as LXA4, increase the microglial expression of CD36 and promote tissue repair in pathologies with an inflammatory component, such as stroke.
authors: 2.Depto. de Farmacología, Facultad de Medicina, Universidad Complutense, Avda. Complutense s/n, 28040 Madrid, Spain. neurona@med.ucm.es.
authors: Iván
authors: I
authors: Ballesteros
authors: María I
authors: MI
authors: Cuartero
authors: Jesús M
authors: JM
authors: Pradillo
authors: Juan
authors: J
authors: de la Parra
authors: Alberto
authors: A
authors: Pérez-Ruiz
authors: Angel
authors: A
authors: Corbí
authors: Mercedes
authors: M
authors: Ricote
authors: John A
authors: JA
authors: Hamilton
authors: Mónica
authors: M
authors: Sobrado
authors: José
authors: J
authors: Vivancos
authors: Florentino
authors: F
authors: Nombela
authors: Ignacio
authors: I
authors: Lizasoain
authors: María A
authors: MA
authors: Moro
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000502:physiology*; D002545:Brain Ischemia / Q000276:immunology; D018955:CD36 Antigens / Q000032:analysis / Q000502:physiology*; D002478:Cells, Cultured; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology*; D044045:Lipoxins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000276:immunology*; D047495:PPAR gamma / Q000819:agonists / Q000502:physiology*; D010587:Phagocytosis; D051381:Rats; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D018955:CD36 Antigens; D007004:Hypoglycemic Agents; D044045:Lipoxins; D047495:PPAR gamma; D045162:Thiazolidinediones; C040527:lipoxin A4; D000077154:Rosiglitazone; D001094:Arachidonate 5-Lipoxygenase
keywords: lipoxin; microglia; phagocytosis; resolution; stroke