The endocannabinoid anandamide mediates anti‐inflammatory effects through activation of NR4A nuclear receptors
Year: 2024
Type: article
Abstract: BACKGROUND AND PURPOSE: Endocannabinoids are lipid mediators, which elicit complex biological effects that extend beyond the central nervous system. Tissue concentrations of endocannabinoids increase in atherosclerosis, and for the endocannabinoid N-arachidonoyl-ethanolamine (anandamide, AEA), this has been linked to an anti-inflammatory function. In this study, we set out to determine the anti-inflammatory mechanism of action of AEA, specifically focusing on vascular smooth muscle cells. EXPERIMENTAL APPROACH: RNA-sequencing, RT-qPCR, LC-MS/MS, NanoBit, ChIP, microscale thermophoresis, NMR structural footprinting, Gal4 reporter gene assays and loss of function approaches in cell and ex vivo organ culture were used. KEY RESULTS: AEA pretreatment attenuated the cytokine-mediated induction of inflammatory gene expression such as CCL2. This effect was also observed in preparations obtained from cannabinoid receptor knockout mice and after pertussis toxin treatment. The anti-inflammatory effect of AEA required preincubation, suggesting an effect through gene induction. AEA increased the expression of the nuclear receptors NR4A1 and NR4A2. Knockdown and knockout of these receptors blocked the AEA-mediated anti-inflammatory effect in cell culture and aortic organ culture, respectively. Conversely, NR4A agonists (CsnB, C-DIM12) attenuated inflammatory gene expression. AEA binds to NR4A, and mutations in NR4A attenuated this effect. The interaction of AEA with NR4A caused recruitment of the nuclear corepressor NCoR1 to the CCL2 promoter, resulting in gene suppression. CONCLUSION AND IMPLICATIONS: By binding to NR4A, AEA elicits an anti-inflammatory response in vascular smooth muscle cells. NR4A-binding by AEA analogues may represent novel anti-inflammatory agents.
Source: British Journal of Pharmacology
DOI: 10.1111/bph.17366
Authors: Tom Teichmann, Beatrice Pflüger‐Müller, Virna Margarita Martín Giménez, Fiona Sailer, Henrik Dirks, Simonida Zehr, Timothy Warwick, Felix Brettner, Paola Munoz‐Tello, Andreas Zimmer, Irmgard Tegeder, Dominique Thomas, Robert Gurke, Stefan Günther, Jan Heering, Ewgenij Proschak, Gerd Geisslinger, Iris‐S. Bibli, Dagmar Meyer zu Heringdorf, Walter Manucha, Maike Windbergs, Stefan Knapp, Andreas Weigert, Matthias S. Leisegang, Douglas Kojetin, Ralf P. Brandes
Institutions: Goethe University Frankfurt, German Centre for Cardiovascular Research, Universidad Católica de Cuyo, Vanderbilt University, University of Bonn, Fraunhofer Institute for Translational Medicine and Pharmacology, Max Planck Institute for Heart and Lung Research, University Hospital Frankfurt, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad Nacional de Cuyo, Instituto de Medicina y Biología Experimental de Cuyo
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,550
Awards: G1502742686, G1537051830, EXC 2026: CardioPulmonary Institute (CPI), G408112445, GRK 2336: Auflösung von Entzündungsreaktionen: Mediatoren, Signaling und Intervention, SFB 1531: Schadenskontrolle durch das Stromavaskuläre Kompartiment, Molecular basis of activation of the orphan nuclear receptor Nurr1
OpenAlex ID: W4404551508