Production of Serotonin by Tryptophan Hydroxylase 1 and Release via Platelets Contribute to Allergic Airway Inflammation

Rationale: 5-Hydroxytryptamine (5-HT) is involved in the pathogenesis of allergic airway inflammation (AAI). It is unclear, however, how 5-HT contributes to AA! and whether this depends on tryptophan hydroxylase (TPH) 1, the critical enzyme for peripheral 5-HT synthesis. Objectives: 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 AAL 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 AA, and in human asthma. Measurements and Main 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.