RT Journal Article
T1 Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy and metabolic reprograming
A1 Angelina Querencias, Alba
A1 Pérez Diego, Mario
A1 López Abente, Jacobo
A1 Rückert, Beate
A1 Nombela, Iván
A1 Akdis, Mübeccel
A1 Martín Fontecha, María del Mar
A1 Akdis, Cezmi A.
A1 Palomares Gracia, Óscar
AB 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.
PB Springer Nature
SN 1933-0219
YR 2021
FD 2021-09-21
LK https://hdl.handle.net/20.500.14352/4473
UL https://hdl.handle.net/20.500.14352/4473
LA eng
NO Received: 5 May 2021 / Revised: 4 August 2021 / Accepted: 7 September 2021 / Published online: 21 September 2021.
NO Ministerio de Economía de España (MINECO)
NO Ministerio de Ciencia e Innovación (MICINN)
NO Swiss National Science Foundation
NO Christine Kühne-Center for Allergy Research and Education (CK-CARE) (Suiza)
DS Docta Complutense
RD 6 oct 2024