title: Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation.
abstract: BACKGROUND
  5-Hydroxytryptamine (5-HT) is involved in the pathogenesis of allergic airway inflammation (AAI). It is unclear, however, how 5-HT contributes to AAI and whether this depends on tryptophan hydroxylase (TPH) 1, the critical enzyme for peripheral 5-HT synthesis.
  
  
  OBJECTIVE
  To elucidate the role of TPH1 and the peripheral source of 5-HT in asthma pathogenesis.
  
  
  METHODS
  TPH1-deficient and TPH1-inhibitor-treated animals were challenged in ovalbumin and house dust mite models of AAI. Experiments with bone marrow chimera, mast cell-deficient animals, platelets transfusion, and bone marrow dendritic cells (BMDC) driven model of AAI were performed. 5-HT levels were measured in bronchoalveolar lavage fluid or serum of animals with AAI and in human asthma.
  
  
  RESULTS
  5-HT levels are increased in bronchoalveolar lavage fluid of mice and people with asthma after allergen provocation. TPH1 deficiency and TPH1 inhibition reduced all cardinal features of AAI. Administration of exogenous 5-HT restored AAI in TPH1-deficient mice. The pivotal role of 5-HT production by structural cells was corroborated by bone marrow chimera experiments. Experiments in mast cell-deficient mice revealed that mast cells are not a source of 5-HT, whereas transfusion of platelets from wild-type and TPH1-deficient mice revealed that only platelets containing 5-HT enhanced AAI. Lack of endogenous 5-HT in vitro and in vivo was associated with an impaired Th2-priming capacity of BMDC.
  
  
  CONCLUSIONS
  In summary, TPH1 deficiency or inhibition reduces AAI. Platelet- and not mast cell-derived 5-HT is pivotal in AAI, and lack of 5-HT leads to an impaired Th2-priming capacity of BMDC. Thus, targeting TPH1 could offer novel therapeutic options for asthma.
authors: Department of Pneumology, University Medical Center Freiburg, Freiburg, Germany.
authors: Thorsten
authors: T
authors: Dürk
authors: Daniel
authors: D
authors: Duerschmied
authors: Tobias
authors: T
authors: Müller
authors: Melanie
authors: M
authors: Grimm
authors: Sebastian
authors: S
authors: Reuter
authors: Rodolfo Paula
authors: RP
authors: Vieira
authors: Korcan
authors: K
authors: Ayata
authors: Sanja
authors: S
authors: Cicko
authors: Stephan
authors: S
authors: Sorichter
authors: Diego J
authors: DJ
authors: Walther
authors: J Christian
authors: JC
authors: Virchow
authors: Christian
authors: C
authors: Taube
authors: Marco
authors: M
authors: Idzko
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D001792:Blood Platelets / Q000276:immunology* / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin; D039981:Pyroglyphidae; D012701:Serotonin / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000276:immunology*
chemical_list: D012701:Serotonin; D010047:Ovalbumin; C497467:TPH1 protein, human; D014365:Tryptophan Hydroxylase