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.

Cell Surface CD36 Protein in Monocyte/Macrophage Contributes to Phagocytosis during the Resolution Phase of Ischemic Stroke in Mice

“…In neonatal stroke, a beneficial role of CD36 by enhancing phagocytosis has been reported (23), suggesting a more permissive and less inflammatory ischemic milieu in stroke during early development. Other studies have shown an association between increased CD36 and enhanced hematoma resolution in hemorrhagic stroke (21,22) and that CD36 plays a role in inflammation resolution after permanent stroke (33), likely reflecting the presence of apoptotic cells that interact with CD36 for phagocytosis. Thus, the functions of CD36 are likely dictated by the ligands available in the ischemic milieu, depending on developmental stages of stroke (neonatal versus adult), types of stroke (ischemic versus hemorrhagic), and specific post-stroke stages (acute inflammatory versus late recovery phases).…”

Iso-α-acids, Bitter Components of Beer, Prevent Inflammation and Cognitive Decline Induced in a Mouse Model of Alzheimer's Disease

“…Activation of PPAR-␥, a nuclear receptor, contributes to the enhancement of microglial phagocytosis (27)(28)(29)(30). PPAR-␥ is known as a drug discovery target to improve resistance to insulin, and pioglitazone, a potent PPAR-␥ agonist (31,32), is used to treat type 2 diabetes (33).…”

Neuroprotective Properties of a Macrolide Antibiotic in a Mouse Model of Middle Cerebral Artery Occlusion: Characterization of the Immunomodulatory Effects and Validation of the Efficacy of Intravenous Administration

“…In fact, preservation of alternatively activated M2 microglia/macrophages promotes neuronal survival and functional recovery under ischemic/hypoxic conditions. [8][9][10][86][87][88] The mechanism by which azithromycin shifts macrophages from the classically activated (M1) to the alternatively activated (M2) phenotype has not been completely elucidated [89][90][91] ; however, AP-1 activation and impairment of lysosomal functions may be probably involved. 92,93 These immunomodulatory properties contribute to the clinical efficacy of azithromycin in respiratory diseases, 25 whereas their relevance in neurodegenerative conditions has only been partially explored.…”