Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor.
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.
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
F
F
Guida
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
L
L
Luongo
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
S
S
Boccella
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
M E
ME
Giordano
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
R
R
Romano
Department of Women, Child and General and Specialistic Surgery, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
G
G
Bellini
Department of Women, Child and General and Specialistic Surgery, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
I
I
Manzo
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
A
A
Furiano
Department of Experimental Medicine, Section of Microbiology and Clinical Microbiology, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
A
A
Rizzo
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Department of Science and Technology, University of Sannio, Benevento, Italy.
R
R
Imperatore
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
F A
FA
Iannotti
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
E
E
D'Aniello
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
F
F
Piscitelli
Department of Women, Child and General and Specialistic Surgery, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.
F
F
Sca Rossi
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
L
L
Cristino
Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
V
V
Di Marzo
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy.
V
V
de Novellis
Department of Experimental Medicine, Section of Pharmacology L. Donatelli, Università degli Studi della Campania "Luigi Vanvitelli" (Ex SUN), 80138, Naples, Italy. sabatino.maione@unina2.it.|Endocannabinoid Research Group, Institute of Biomolecular Chemistry, C.N.R., Pozzuoli, Italy. sabatino.maione@unina2.it.
S
S
Maione
D000577:Amides; D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D004983:Ethanolamines / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010169:Palmitic Acids / Q000494:pharmacology*; D010587:Phagocytosis / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism*
D000577:Amides; D004983:Ethanolamines; D047493:PPAR alpha; D010169:Palmitic Acids; D012333:RNA, Messenger; D043885:Receptor, Cannabinoid, CB2; C005958:palmidrol