Angelina Querencias, AlbaPérez Diego, MarioLópez Abente, JacoboRückert, BeateNombela, IvánAkdis, MübeccelMartín Fontecha, María del MarAkdis, Cezmi A.Palomares, Oscar2023-06-162023-06-162021-09-211933-021910.1038/s41385-021-00455-xhttps://hdl.handle.net/20.500.14352/4473Received: 5 May 2021 / Revised: 4 August 2021 / Accepted: 7 September 2021 / Published online: 21 September 2021.The generation of functional regulatory T cells (Tregs) is essential to keep tissue homeostasis and restore healthy immune responses in many biological and inflammatory contexts. Cannabinoids have been pointed out as potential therapeutic tools for several diseases. Dendritic cells (DCs) express the endocannabinoid system, including the cannabinoid receptors CB1 and CB2. However, how cannabinoids might regulate functional properties of DCs is not completely understood. We uncover that the triggering of cannabinoid receptors promote human tolerogenic DCs that are able to prime functional FOXP3+ Tregs in the context of different inflammatory diseases. Mechanistically, cannabinoids imprint tolerogenicity in human DCs by inhibiting NF-κB, MAPK and mTOR signalling pathways while inducing AMPK and functional autophagy flux via CB1- and PPARα-mediated activation, which drives metabolic rewiring towards increased mitochondrial activity and oxidative phosphorylation. Cannabinoids exhibit in vivo protective and anti-inflammatory effects in LPS-induced sepsis and also promote the generation of FOXP3+ Tregs. In addition, immediate anaphylactic reactions are decreased in peanut allergic mice and the generation of allergen-specific FOXP3+ Tregs are promoted, demonstrating that these immunomodulatory effects take place in both type 1- and type 2-mediated inflammatory diseases. Our findings might open new avenues for novel cannabinoid-based interventions in different inflammatory and immune-mediated diseases.engAtribución 3.0 Españajournal articlehttps://doi.org/10.1038/s41385-021-00455-xhttp://www.nature.com/mi/open access577.27577.121612.112612.017633.888Regulatory T-cellsHuman dendritic cellsActivationMTORAMPKMechanismsResponsesDifferentiationExpressionCapacityBiología celular (Biología)Biología molecular (Biología)Bioquímica (Biología)2407 Biología Celular2415 Biología Molecular2302 Bioquímica