The endocannabinoid anandamide mediates antiinflammatory effects through activation of NR4A nuclear receptors

TOM TEICHMANN; VIRNA MARGARITA MARTÍN GIMENÉZ; WALTER MANUCHA; RALF BRANDES

BRITISH JOURNAL OF PHARMACOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2024

0007-1188

Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. The tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide; AEA), this has been linked to a potential anti-inflammatory function. Focusing on vascular smooth muscle cells, we set out to determine the underlying mechanism. Confirming previous results, AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression like CCL2. Unexpectedly, this effect was also observed in preparations of cannabinoid receptor (CB) 1 and 2 knockout mice and after pertussis toxin treatment but was restricted to fairly high concentrations of the lipid. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. RNA-seq revealed that AEA caused an increased expression of the nuclear receptors NR4A1 and NR4A2. Knockdown of these receptors blocked the AEA-mediated anti-inflammatory effect. Conversely, NR4A agonists (CsnB, C-DIM12) also attenuated inflammatory gene expression. Microscale thermophoresis, NMR-spectroscopy, and Gal4 reporter gene assays confirmed the binding of AEA to NR4A. Moreover, AEA caused an NR4A-dependent recruitment of the nuclear corepressor NCoR1 to the CCL2 promotor. Finally, AEA also elicited anti-inflammatory effects in the vascular organ culture of mice, which was not observed after the genetic deletion of NR4A1 or NR4A2.AEA elicits a specific anti-inflammatory response in vascular smooth muscle cells through activation of NR4A. AEA analogous with high potential to bind NR4A receptors might act as novel anti-inflammatory drugs.