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

Autor:	Espinosa-Riquer ZP; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico., Ibarra-Sánchez A; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico., Vibhushan S; INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.; CNRS ERL8252, 75018 Paris, France; and.; Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France., Bratti M; INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.; CNRS ERL8252, 75018 Paris, France; and.; Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France., Charles N; INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.; CNRS ERL8252, 75018 Paris, France; and.; Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France., Blank U; INSERM U1149, Centre de Recherche sur l'Inflammation, 75018 Paris, France.; CNRS ERL8252, 75018 Paris, France; and.; Laboratoire d'Excellence Inflamex, Faculté de Médecine Xavier Bichat, Sorbonne Paris Cité, Université Paris Diderot, 75018 Paris, France., Rodríguez-Manzo G; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico; cgonzal@cinvestav.mx grodrigu@cinvestav.mx., González-Espinosa C; Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, CP 14330 Mexico City, Mexico; cgonzal@cinvestav.mx grodrigu@cinvestav.mx.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2019 Apr 15; Vol. 202 (8), pp. 2360-2371. Date of Electronic Publication: 2019 Feb 27.
DOI:	10.4049/jimmunol.1800997
Abstrakt:	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 responses in vivo. (Copyright © 2019 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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