Platelet-derived serotonin links vascular disease and tissue fibrosis.: Serotonin in 5-HT2B fibrotic disease

Clara Dees 1 Alfiya Akhmetshina 1 Pawel Zerr 1 Nicole Reich 1 Katrin Palumbo 1 Angelika Horn 1 Astrid Jüngel 2 Christian Beyer 1 Gerhard Krönke 1 Jochen Zwerina 1 Rudolf Reiter 3 Natalia Alenina 4 Luc Maroteaux 5 Stephen Gay 2 Georg Schett 1 Oliver Distler 2 Jörg Distler 1, *
* Auteur correspondant
1 Department of Internal Medicine 3
2 Center of Experimental Rheumatology
3 ErgoNex Pharma GmbH
4 Max Delbrück Center for Molecular Medicine Berlin
5 Institut du Fer à Moulin
Abstract : Vascular damage and platelet activation are associated with tissue remodeling in diseases such as systemic sclerosis, but the molecular mechanisms underlying this association have not been identified. In this study, we show that serotonin (5-hydroxytryptamine [5-HT]) stored in platelets strongly induces extracellular matrix synthesis in interstitial fibroblasts via activation of 5-HT(2B) receptors (5-HT(2B)) in a transforming growth factor β (TGF-β)-dependent manner. Dermal fibrosis was reduced in 5-HT(2B)(-/-) mice using both inducible and genetic models of fibrosis. Pharmacologic inactivation of 5-HT(2B) also effectively prevented the onset of experimental fibrosis and ameliorated established fibrosis. Moreover, inhibition of platelet activation prevented fibrosis in different models of skin fibrosis. Consistently, mice deficient for TPH1, the rate-limiting enzyme for 5-HT production outside the central nervous system, showed reduced experimental skin fibrosis. These findings suggest that 5-HT/5-HT(2B) signaling links vascular damage and platelet activation to tissue remodeling and identify 5-HT(2B) as a novel therapeutic target to treat fibrotic diseases.
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Journal of Experimental Medicine, Rockefeller University Press, 2011, 208 (5), pp.961-972. 〈10.1084/jem.20101629 〉
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Clara Dees, Alfiya Akhmetshina, Pawel Zerr, Nicole Reich, Katrin Palumbo, et al.. Platelet-derived serotonin links vascular disease and tissue fibrosis.: Serotonin in 5-HT2B fibrotic disease. Journal of Experimental Medicine, Rockefeller University Press, 2011, 208 (5), pp.961-972. 〈10.1084/jem.20101629 〉. 〈inserm-00589662〉

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