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Stimulation of nAchRα7 Receptor Inhibits TNF Synthesis and Secretion in Response to LPS Treatment of Mast Cells by Targeting ERK1/2 and TACE Activation

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Abstract

The cholinergic anti-inflammatory pathway is recognized as one of the main mechanisms of neuromodulation of the immune system. Activation of the α7 nicotinic acetylcholine receptor (nAchRα7) suppresses cytokine synthesis in distinct immune cells but the molecular mechanisms behind this effect remain to be fully described. Mast cells (MCs) are essential players of allergic reactions and innate immunity responses related to chronic inflammation. Activation of TLR4 receptor in MCs leads to the rapid secretion of pre-synthesized TNF from intracellular pools and to the activation of NFκB, necessary for de novo synthesis of TNF and other cytokines. Here we report that the nAchRα7 receptor specific agonist GTS-21 inhibits TLR4-induced secretion of preformed TNF from MCs in vivo and in vitro. Utilizing bone marrow-derived mast cells (BMMCs) it was found that GTS-21 also diminished secretion of de novo synthesized TNF, TNF mRNA accumulation and IKK-dependent p65-NFκB phosphorylation in response to LPS. nAchRα7 triggering prevented TLR4-induced ERK1/2 phosphorylation, which resulted an essential step for TNF secretion due to the phosphorylation of the metallopeptidase responsible for TNF maturation (TACE). Main inhibitory actions of GTS-21 were prevented by AG490, an inhibitor of JAK-2 kinase. Our results show for the first time, that besides the prevention of NFκB-dependent transcription, inhibitory actions of nAchRα7 triggering include the blockade of pathways leading to exocytosis of granule-stored cytokines in MCs.

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Acknowledgments

This research was supported by Conacyt-ANR 188565 and Conacyt 1122 Grants to CGE. Grant Conacyt 155255 to CLR. FGM received a scholarship from Conacyt 243361. FGM performed all the experiments. CGE and CLR contributed to study design and analysis of the data. Authors want to thank Alfredo Ibarra Sánchez for generation of BMMCs and technical assistance in different assays, Iván Galván Mendoza for confocal microscopy assistance. We also thank Dr. Jorge Fernández Hernández, Ma. Antonieta López López, Ricardo Gaxiola Centeno, Víctor Manuel García Gómez, Benjamín E. Chávez Álvarez, Juan R. Martínez Parente Ricaud and Ramón Gómez Martínez for their assistance in maintaining the colonies of mice (Unit the Production and Experimental of Laboratory Animals (UPEAL, Cinvestav).

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  1. Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav), Sede Sur, Calzada de los Tenorios No 235, Colonia Granjas Coapa, Tlalpan, CP 14330, Ciudad de México, Mexico

    F. Guzmán-Mejía, C. López-Rubalcava & C. González-Espinosa

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  1. F. Guzmán-Mejía
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Guzmán-Mejía, F., López-Rubalcava, C. & González-Espinosa, C. Stimulation of nAchRα7 Receptor Inhibits TNF Synthesis and Secretion in Response to LPS Treatment of Mast Cells by Targeting ERK1/2 and TACE Activation. J Neuroimmune Pharmacol 13, 39–52 (2018). https://doi.org/10.1007/s11481-017-9760-7

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