• Am. J. Respir. Crit. Care Med. · Mar 2013

    Production of serotonin by tryptophan hydroxylase 1 and release via platelets contribute to allergic airway inflammation.

    • Thorsten Dürk, Daniel Duerschmied, Tobias Müller, Melanie Grimm, Sebastian Reuter, Rodolfo Paula Vieira, Korcan Ayata, Sanja Cicko, Stephan Sorichter, Diego J Walther, J Christian Virchow, Christian Taube, and Marco Idzko.
    • Department of Pneumology, University Medical Center Freiburg, Freiburg, Germany.
    • Am. J. Respir. Crit. Care Med. 2013 Mar 1; 187 (5): 476-85.

    Rationale5-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.ObjectivesTo elucidate the role of TPH1 and the peripheral source of 5-HT in asthma pathogenesis.MethodsTPH1-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.Measurements And Main Results5-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.ConclusionsIn 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.

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