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TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages

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Abstract

Trace amine-associated receptor 1 (TAAR1) is an established neuroregulatory G protein-coupled receptor with recent studies suggesting additional functions related to immunomodulation. Our lab has previously investigated TAAR1 expression within cells of the innate immune system and herein we aim to further elucidate TAAR1 function in both peripherally-derived and CNS-resident macrophages. The selective TAAR1 agonist RO5256390 was used in combination with common damage associated molecular patterns (ATP and ADP) to observe the effect of TAAR1 agonism on modulating cytokine secretion and metabolic profiles. In mouse bone-marrow derived macrophages, TAAR1 agonism inhibited TNF secretion following ATP stimulation, which appeared to be downstream of an associated pro-inflammatory shift in metabolic profile and transcriptional regulation of TNF synthesis. In contrast, TAAR1 agonism had no effect on ADP-induced TNF and IL-6 secretion in mouse microglia in either the presence or absence of astrocytes. In summary, we report a novel interaction between TAAR1 and purinergic signaling in peripherally-derived, but not CNS-resident, macrophages. These findings provide the first evidence of trace aminergic and purinergic crosstalk, and support the potential for TAAR1 as a novel therapeutic target in inflammatory disorders.

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Acknowledgements

Special thanks to Tangyne Berry, Neva Fudge, and Brad Williams for their expert technical assistance in sample preparation and storage.

Funding

This research was funded by the Natural Sciences and Engineering Research Council (RGPIN-2016–04164 & RGPIN-2018–06201) and the Canada Research Chairs Program (950–232601).

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Science, Memorial University of Newfoundland, 232 Elizabeth Ave, St. John’s, NL, A1B 3X9, Canada

    David A. Barnes & Mark D. Berry

  2. Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, 300 Prince Philip Drive, St. John’s, NL, A1B 3V6, Canada

    David A. Barnes & Craig S. Moore

  3. Neuroscience and Rare Diseases Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, 4070, Basel, Switzerland

    Marius C. Hoener

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  1. David A. Barnes
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  4. Mark D. Berry
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Contributions

Conceptualization, David A. Barnes, Craig S. Moore, and Mark D. Berry; Methodology, David A. Barnes, Craig S. Moore, and Mark D. Berry; Validation, David A. Barnes; Formal Analysis, David A. Barnes; Investigation, David A. Barnes, Craig S. Moore, and Mark D. Berry; Resources, Marius C. Hoener, Craig S. Moore, and Mark D. Berry; Data Curation, David A. Barnes, Craig S. Moore, and Mark D. Berry; Writing – Original Draft Preparation, David A. Barnes; Writing – Review & Editing, David A. Barnes, Marius C. Hoener, Craig S. Moore, and Mark D. Berry; Visualization, David A. Barnes; Supervision, Craig S. Moore and Mark D. Berry; Project Administration, David A. Barnes, Craig S. Moore, and Mark D. Berry; Funding Acquisition, Craig S. Moore and Mark D. Berry.

Corresponding author

Correspondence to Mark D. Berry.

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Ethical Approval

All animal experiments were approved by the Memorial University Animal Care Committee in accordance with the Canadian Council on Animal Care guidelines.

Conflict of Interest

Marius C. Hoener is an employee of F. Hoffman-La Roche Ltd., Basel, Switzerland.

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Barnes, D.A., Hoener, M.C., Moore, C.S. et al. TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages. J Neuroimmune Pharmacol 18, 100–111 (2023). https://doi.org/10.1007/s11481-022-10053-8

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  • DOI: https://doi.org/10.1007/s11481-022-10053-8

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