title: Platelet-derived serotonin links vascular disease and tissue fibrosis.
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.
authors.affiliation: Department of Internal Medicine 3, Institute for Clinical Immunology, University of Erlangen-Nuremberg, 91054 Erlangen, Germany.
authors.forename: Clara
authors.initials: C
authors.lastname: Dees
authors.forename: Alfiya
authors.initials: A
authors.lastname: Akhmetshina
authors.forename: Pawel
authors.initials: P
authors.lastname: Zerr
authors.forename: Nicole
authors.initials: N
authors.lastname: Reich
authors.forename: Katrin
authors.initials: K
authors.lastname: Palumbo
authors.forename: Angelika
authors.initials: A
authors.lastname: Horn
authors.forename: Astrid
authors.initials: A
authors.lastname: Jüngel
authors.forename: Christian
authors.initials: C
authors.lastname: Beyer
authors.forename: Gerhard
authors.initials: G
authors.lastname: Krönke
authors.forename: Jochen
authors.initials: J
authors.lastname: Zwerina
authors.forename: Rudolf
authors.initials: R
authors.lastname: Reiter
authors.forename: Natalia
authors.initials: N
authors.lastname: Alenina
authors.forename: Luc
authors.initials: L
authors.lastname: Maroteaux
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.forename: Georg
authors.initials: G
authors.lastname: Schett
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015539:Platelet Activation / Q000235:genetics; D044403:Receptor, Serotonin, 5-HT2B / Q000235:genetics / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D044403:Receptor, Serotonin, 5-HT2B; D016212:Transforming Growth Factor beta; D012701:Serotonin