Production of Serotonin by Tryptophan Hydroxylase 1 and Release via Platelets Contribute to Allergic Airway Inflammation
| Autor: | Korcan Ayata, Tobias Müller, Rodolfo de Paula Vieira, Thorsten Dürk, Sebastian Reuter, Diego J. Walther, Melanie Grimm, Stephan Sorichter, Daniel Duerschmied, Sanja Cicko, Marco Idzko, Christian Taube, J. Christian Virchow |
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| Rok vydání: | 2013 |
| Předmět: |
Blood Platelets
Pulmonary and Respiratory Medicine Serotonin medicine.medical_specialty Ovalbumin Mice Transgenic Tryptophan Hydroxylase Critical Care and Intensive Care Medicine Pathogenesis Mice Internal medicine Animals Humans Medicine Mast Cells Mice Knockout House dust mite TPH1 medicine.diagnostic_test biology business.industry Pyroglyphidae Dendritic Cells Tryptophan hydroxylase biology.organism_classification Asthma respiratory tract diseases Mice Inbred C57BL Bronchoalveolar lavage medicine.anatomical_structure Endocrinology platelets Immunology biology.protein tryptophan hydroxylase 1 Bone marrow business Bronchoalveolar Lavage Fluid |
| Zdroj: | American Journal of Respiratory and Critical Care Medicine, 187(5), 476-485 |
| ISSN: | 1535-4970 1073-449X |
| Popis: | 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.To elucidate the role of TPH1 and the peripheral source of 5-HT in asthma pathogenesis.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.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.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. |
| Databáze: | OpenAIRE |
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