PMID- 34548620
OWN - NLM
STAT- MEDLINE
DCOM- 20220401
LR  - 20230203
IS  - 1935-3456 (Electronic)
IS  - 1933-0219 (Print)
IS  - 1933-0219 (Linking)
VI  - 15
IP  - 1
DP  - 2022 Jan
TI  - Cannabinoids induce functional Tregs by promoting tolerogenic DCs via autophagy 
      and metabolic reprograming.
PG  - 96-108
LID - 10.1038/s41385-021-00455-x [doi]
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-kappaB, MAPK and mTOR signalling 
      pathways while inducing AMPK and functional autophagy flux via CB1- and 
      PPARalpha-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.
CI  - (c) 2021. The Author(s).
FAU - Angelina, Alba
AU  - Angelina A
AD  - Department of Biochemistry and Molecular Biology, School of Chemistry, 
      Complutense University of Madrid, Madrid, Spain.
FAU - Perez-Diego, Mario
AU  - Perez-Diego M
AD  - Department of Biochemistry and Molecular Biology, School of Chemistry, 
      Complutense University of Madrid, Madrid, Spain.
FAU - Lopez-Abente, Jacobo
AU  - Lopez-Abente J
AD  - Department of Biochemistry and Molecular Biology, School of Chemistry, 
      Complutense University of Madrid, Madrid, Spain.
FAU - Ruckert, Beate
AU  - Ruckert B
AD  - Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 
      Davos, Switzerland.
FAU - Nombela, Ivan
AU  - Nombela I
AD  - Department of Biochemistry and Molecular Biology, School of Chemistry, 
      Complutense University of Madrid, Madrid, Spain.
FAU - Akdis, Mubeccel
AU  - Akdis M
AD  - Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 
      Davos, Switzerland.
FAU - Martin-Fontecha, Mar
AU  - Martin-Fontecha M
AD  - Department of Organic Chemistry, School of Optics and Optometry, Complutense 
      University of Madrid, Madrid, Spain.
FAU - Akdis, Cezmi
AU  - Akdis C
AD  - Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, 
      Davos, Switzerland.
FAU - Palomares, Oscar
AU  - Palomares O
AD  - Department of Biochemistry and Molecular Biology, School of Chemistry, 
      Complutense University of Madrid, Madrid, Spain. oscar.palomares@quim.ucm.es.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210921
PL  - United States
TA  - Mucosal Immunol
JT  - Mucosal immunology
JID - 101299742
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Cannabinoids)
RN  - 0 (Indoles)
RN  - 0 (Receptor, Cannabinoid, CB1)
RN  - 0 (Receptor, Cannabinoid, CB2)
RN  - RML78EN3XE (Rimonabant)
RN  - U1LNJ6NBKA (iodopravadoline)
SB  - IM
MH  - Anaphylaxis/*prevention & control
MH  - Animals
MH  - Anti-Inflammatory Agents
MH  - Autophagy
MH  - Cannabinoids/*therapeutic use
MH  - Cells, Cultured
MH  - Cellular Reprogramming
MH  - Coculture Techniques
MH  - Dendritic Cells/immunology/*metabolism
MH  - Humans
MH  - Hypersensitivity/*drug therapy
MH  - Immune Tolerance
MH  - Indoles/pharmacology
MH  - Mice
MH  - Oxidative Phosphorylation
MH  - Receptor, Cannabinoid, CB1/agonists/*metabolism
MH  - Receptor, Cannabinoid, CB2/agonists/*metabolism
MH  - Rimonabant/pharmacology
MH  - Signal Transduction
MH  - T-Lymphocytes, Regulatory/*immunology
MH  - Th1-Th2 Balance
PMC - PMC8732281
COIS- C.A. reports grants from Allergopharma, grants from Idorsia, Swiss National 
      Science Foundation, Christine Kuhne-Center for Allergy Research and Education, 
      European Commission's Horison's 2020 Framework Programme, Cure, Novartis Research 
      Institutes, Astra Zeneca, Scibase, advisory role in Sanofi/Regeneron, grants from 
      Glakso Smith-Kline, advisory role in Scibase. O.P. received research grants from 
      Inmunotek S.L., Novartis and MINECO and fees for giving scientific lectures or 
      participation in Advisory Boards from: Allergy Therapeutics, Amgen, AstraZeneca, 
      Diater, GlaxoSmithKline, S.A, Inmunotek S.L, Novartis, Sanofi-Genzyme and 
      Stallergenes. The rest of authors declare no conflict of interests.
EDAT- 2021/09/23 06:00
MHDA- 2022/04/02 06:00
PMCR- 2021/09/21
CRDT- 2021/09/22 07:00
PHST- 2021/05/05 00:00 [received]
PHST- 2021/09/07 00:00 [accepted]
PHST- 2021/08/04 00:00 [revised]
PHST- 2021/09/23 06:00 [pubmed]
PHST- 2022/04/02 06:00 [medline]
PHST- 2021/09/22 07:00 [entrez]
PHST- 2021/09/21 00:00 [pmc-release]
AID - S1933-0219(22)00030-7 [pii]
AID - 455 [pii]
AID - 10.1038/s41385-021-00455-x [doi]
PST - ppublish
SO  - Mucosal Immunol. 2022 Jan;15(1):96-108. doi: 10.1038/s41385-021-00455-x. Epub 
      2021 Sep 21.