Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor

Abstract

The endogenous fatty acid amide palmitoylethanolamide (PEA) has been shown to exert anti-inflammatory actions mainly through inhibition of the release of pro-inflammatory molecules from mast cells, monocytes and macrophages. Indirect activation of the endocannabinoid (eCB) system is among the several mechanisms of action that have been proposed to underlie the different effects of PEA in vivo. In this study, we used cultured rat microglia and human macrophages to evaluate whether PEA affects eCB signaling. PEA was found to increase CB2 mRNA and protein expression through peroxisome proliferator-activated receptor-α (PPAR-α) activation. This novel gene regulation mechanism was demonstrated through: (i) pharmacological PPAR-α manipulation, (ii) PPAR-α mRNA silencing, (iii) chromatin immunoprecipitation. Moreover, exposure to PEA induced morphological changes associated with a reactive microglial phenotype, including increased phagocytosis and migratory activity. Our findings suggest indirect regulation of microglial CB2R expression as a new possible mechanism underlying the effects of PEA. PEA can be explored as a useful tool for preventing/treating the symptoms associated with neuroinflammation in CNS disorders.

Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome

“…PEA, as an endogenous compound, has a double therapeutic effect (that is, anti-nociceptive and anti-inflammatory) without adverse effects at pharmacologically relevant doses [10, 11]. Recent report highlights a new PEA potential mechanism of action mediated by the induction of the CB2 up-regulation [12]. The large particle size and lipidic nature of PEA limit its solubility and bioavailability.…”

An Aqueous Extract of Herbal Medicine ALWPs Enhances Cognitive Performance and Inhibits LPS-Induced Neuroinflammation via FAK/NF-κB Signaling Pathways

“…Microglial cell migration is associated with neuroinflammation. Specifically, microglial migration and the related phagocytic activity can be activated by G-coupled receptors, which include chemokines ( Guida et al, 2017 ). A recent study demonstrated that the chemokine CCL2 modulates microglial cell migration through the MEK/ERK and PI3K pathways ( Bose et al, 2016 ).…”

How to reprogram microglia toward beneficial functions

“…Although microglia express a wide range of lipid‐sensitive receptors and lipid metabolism‐related genes (Mauerer, Walczak, & Langmann, ; Mecha et al, ), the molecular link between bioactive fatty acids and their effects in microglia has not been completely clarified yet. Emerging evidence suggests that PUFAs can drive a protective phenotype through the activation of CB2, which is among microglial receptors reprogramming microglia toward beneficial function (Guida et al, ; Mecha et al, ; Nunez et al, ) but other receptors may be involved including ALX/FPR2 receptors (Bisicchia et al, ) (Figure ).…”

“…Although microglia express a wide range of lipidsensitive receptors and lipid metabolism-related genes (Mauerer, Walczak, & Langmann, 2009;Mecha et al, 2015), the molecular link between bioactive fatty acids and their effects in microglia has not been completely clarified yet. Emerging evidence suggests that PUFAs can drive a protective phenotype through the activation of CB2, which is among microglial receptors reprogramming microglia toward beneficial function (Guida et al, 2017;Mecha et al, 2015;Nunez et al, 2004) (Ghosh et al, 2017), also dietary lipids may likely shape microglia phenotype acting on cell metabolism. In support to this hypothesis, fasting and ketogenic diet, that lead to a sustained reduction in blood glucose levels and to an increase in circulating ketones, have been reported to have anti-inflammatory actions and suppress activation of microglia by regulating their metabolic features (Longo & Mattson, 2014).…”