Role of prostaglandin E2 as a neuro-immune mediator in the cholinergic anti-inflammatory pathway
Author: Revathikumar, Priya
Date: 2017-05-12
Location: Center for Molecular Medicine Lecture hall, L8:00, Karolinska Universitetssjukhuset, Solna.
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
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Thesis (4.124Mb)
Abstract
Therapeutic implications of cholinergic anti-inflammatory pathway (CAP) activation have marked the beginning of a novel treatment strategy of passing electrical impulses along the left vagus nerve to alleviate acute and chronic inflammatory conditions. Extensive work in understanding CAP through vagus nerve stimulation (VNS) have identified key molecular and cellular mechanisms involved in the α7 nicotinic acetylcholine receptor (nAChR) mediated control of inflammation. Interestingly, recent studies have implicated a role of prostaglandin E2 (PGE2), whose concentration is increased locally following α7 nAChR activation, in this neuro-immune crosstalk. PGE2 is a potent lipid mediator produced by the action of cyclooxygenase enzymes (COX-1/2) and other specific downstream enzymes such as microsomal prostaglandin synthase-1 (mPGES-1) on the phospholipase-released arachidonic acid. While the role of PGE2 during inflammation is still debated, it has now gained fresh impetus owing to recent findings on its role in resolving inflammation. In addition, our knowledge concerning the role of PGE2 in the immunomodulatory effects of CAP is limited. Here, we have investigated the importance of PGE2 in the cholinergic regulation of inflammation by performing both in vivo and in vitro studies with mPGES-1 gene deleted (mPGES-1 (-/-)) mice and human astroglial cells subjected to VNS and nicotine treatment respectively. We observed that inducible PGE2 production is crucial for VNS mediated splenic cholinergic synthesis and immunosuppressive effects during endotoxemia. These observations were applicable only to the splenic portion of the CAP, since VNSinduced norepinephrine release from the splenic nerve was not dependent on PGE2, nor was the expression of b2-adrenergic receptors (AR) on effector T lymphocytes. Importantly, mPGES-1 pharmacological inhibition reversed nicotine immunomodulatory effects in LPS activated human peripheral blood mononuclear cells. Interestingly, while VNS did not affect the COX-1/2 expression, hypothalamic mPGES-1 was found to be elevated. In addition, COX-2 mediated PGE2 is involved in the cholinergic suppression of reactive astrogliosis and neuroinflammatory conditions. In conclusion, we propose that PGE2, which is known to drive febrile response and inflammatory pain during early stages of inflammation, can also have a regulatory role in the cholinergic immune regulation.
List of papers:
I. Le Maître, E., Revathikumar, P., Idborg, H., Raouf, J., Korotkova, M., Jakobsson, P. J., Lampa, J. Impaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase-1 deficient mice. Prostaglandins & other lipid mediators. 2015; 121: 155-62.
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II. Revathikumar, P., Karmakar, U., Estelius, J., Le Maître, E., Korotkova, M., Jakobsson, P. J., Lampa, J. Microsomal Prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of cholinergic antiinflammatory pathway in endotoxemic mouse spleen. [Manuscript]
III. Revathikumar, P., Le Maître, E., Korotkova, M., Hökfelt, T., Svensson, C., Jakobsson, P. J., Lampa, J. Vagus nerve stimulation augments microsomal prostaglandin synthase-1 protein expression and inhibits substance P expression in specific regions of the endotoxemic mice brain. [Manuscript]
IV. Revathikumar, P., Bergqvist, F., Gopalakrishnan, S., Korotkova, M., Jakobsson, P. J., Lampa, J., Le Maître, E. Immunomodulatory effects of nicotine on interleukin 1β activated human astrocytes and the role of cyclooxygenase 2 in the underlying mechanism. Journal of Neuroinflammation. 2016;13: 1-13.
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Pubmed
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I. Le Maître, E., Revathikumar, P., Idborg, H., Raouf, J., Korotkova, M., Jakobsson, P. J., Lampa, J. Impaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase-1 deficient mice. Prostaglandins & other lipid mediators. 2015; 121: 155-62.
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Revathikumar, P., Karmakar, U., Estelius, J., Le Maître, E., Korotkova, M., Jakobsson, P. J., Lampa, J. Microsomal Prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of cholinergic antiinflammatory pathway in endotoxemic mouse spleen. [Manuscript]
III. Revathikumar, P., Le Maître, E., Korotkova, M., Hökfelt, T., Svensson, C., Jakobsson, P. J., Lampa, J. Vagus nerve stimulation augments microsomal prostaglandin synthase-1 protein expression and inhibits substance P expression in specific regions of the endotoxemic mice brain. [Manuscript]
IV. Revathikumar, P., Bergqvist, F., Gopalakrishnan, S., Korotkova, M., Jakobsson, P. J., Lampa, J., Le Maître, E. Immunomodulatory effects of nicotine on interleukin 1β activated human astrocytes and the role of cyclooxygenase 2 in the underlying mechanism. Journal of Neuroinflammation. 2016;13: 1-13.
Fulltext (DOI)
Pubmed
View record in Web of Science®
Institution: Karolinska Institutet
Supervisor: Lampa, Jon
Co-supervisor: Korotkova, Marina; Le Maître, Erwan
Issue date: 2017-04-19
Rights:
Publication year: 2017
ISBN: 978-91-7676-638-5
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