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CCL2 Induces the Production of β2 Adrenergic Receptors and Modifies Astrocytic Responses to Noradrenaline

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Abstract

The decline in brain noradrenaline levels is associated with the progression of certain neurodegenerative diseases. This seems to be due, at least in part, to the ability of noradrenaline to limit glial activation and to reduce the damage associated with it. Our previous studies of the mechanisms involved in this process indicate that noradrenaline induces the production of the chemokine CCL2 in astrocytes. While CCL2 can protect neurons against certain injuries, its overproduction has also proven to be harmful and to prevent noradrenaline neuroprotective effects. Therefore, in this study, we analyze if the modifications caused to astrocytes by an excessive production of CCL2 may alter their response to noradrenaline. Using primary cultures of rat cortical astrocytes, we observed that CCL2 enhances the production of beta 2 adrenergic receptors in these cells. While this potentiates noradrenaline signaling through cAMP, the activation of the transcription factor CREB is inhibited by CCL2. Furthermore, although CCL2 potentiates noradrenaline induction of glycogenolysis, this does not translate into an augmented release of lactate, one of the processes through which astrocytes help support neurons. Additionally, other neuroprotective actions of noradrenaline, such as the production of brain derived neurotrophic factor and the inhibition of the inducible nitric oxide synthase in astrocytes were modified by CCL2. These data suggest that some of the central nervous system alterations related to CCL2 could be due to its effects on adrenergic receptors and its interference with noradrenaline signaling.

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Acknowledgements

The authors are indebted to Dr. Dominique Leprince for supplying the reporter luciferase construct for β2AR.

Funding

This work was supported by the UCM (PR26/16-20278), the Spanish Ministry of Science (SAF2017-86620-R) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). MGP was supported by a Fellowship from the European Youth Employment Initiative (YEI). BGB and JRC are Ramón y Cajal fellows (Spanish Ministry of Economy, Industry and Competitiveness).

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Author notes

  1. Irene L. Gutiérrez and Marta González-Prieto contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid (UCM), Av. Complutense s/n, 28040, Madrid, Spain

    Irene L. Gutiérrez, Marta González-Prieto, Borja García-Bueno, Javier R. Caso & José L. M. Madrigal

  2. Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Investigación Neuroquímica (IUINQ-UCM) and Instituto de Investigación Sanitaria Hospital 12 de Octubre (Imas12), Madrid, Spain

    Irene L. Gutiérrez, Marta González-Prieto, Borja García-Bueno, Javier R. Caso & José L. M. Madrigal

  3. Department of Anesthesiology, University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, IL, 60612, USA

    Douglas L. Feinstein

  4. Dpto. Farmacología, Fac. Medicina, Avda. Complutense s/n, 28040, Madrid, Spain

    José L. M. Madrigal

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  1. Irene L. Gutiérrez
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  6. José L. M. Madrigal
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Correspondence to José L. M. Madrigal.

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Gutiérrez, I.L., González-Prieto, M., García-Bueno, B. et al. CCL2 Induces the Production of β2 Adrenergic Receptors and Modifies Astrocytic Responses to Noradrenaline. Mol Neurobiol 55, 7872–7885 (2018). https://doi.org/10.1007/s12035-018-0960-9

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