TLR4 Receptor Induces 2-AG-Dependent Tolerance to Lipopolysaccharide and Trafficking of CB2 Receptor in Mast Cells

The Journal of Immunology : Official Journal of the American Association of Immunologists
Zyanya P Espinosa-RiquerClaudia González-Espinosa

Abstract

Mast cells (MCs) contribute to the control of local inflammatory reactions and become hyporesponsive after prolonged TLR4 activation by bacterial LPS. The molecular mechanisms involved in endotoxin tolerance (ET) induction in MCs are not fully understood. In this study, we demonstrate that the endocannabinoid 2-arachidonoylglycerol (2-AG) and its receptor, cannabinoid receptor 2 (CB2), play a role in the establishment of ET in bone marrow-derived MCs from C57BL/6J mice. We found that CB2 antagonism prevented the development of ET and that bone marrow-derived MCs produce 2-AG in a TLR4-dependent fashion. Exogenous 2-AG induced ET similarly to LPS, blocking the phosphorylation of IKK and the p65 subunit of NF-κB and inducing the synthesis of molecular markers of ET. LPS caused CB2 receptor trafficking in Rab11-, Rab7-, and Lamp2-positive vesicles, indicating recycling and degradation of the receptor. 2-AG also prevented LPS-induced TNF secretion in vivo, in a MC-dependent model of endotoxemia, demonstrating that TLR4 engagement leads to 2-AG secretion, which contributes to the negative control of MCs activation. Our study uncovers a functional role for the endocannabinoid system in the inhibition of MC-dependent innate immune res...Continue Reading

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Citations

Apr 23, 2020·International Journal of Molecular Sciences·Adam StasiulewiczAnd Joanna I Sulkowska
Feb 27, 2020·International Journal of Molecular Sciences·David O Lyons, Nicholas A Pullen
May 13, 2020·PPAR Research·Oxana Yu KytikovaTatyana A Gvozdenko
May 1, 2021·International Journal of Molecular Sciences·Estefanía MorenoEnric I Canela
Jun 3, 2021·Cells·Mariantonia BraileStefania Loffredo
Jun 12, 2021·Cannabis and Cannabinoid Research·Clare T Johnson, Heather B Bradshaw

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