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

Abstract:

RATIONALE: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. 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 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 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

Dürk T,Duerschmied D,Müller T,Grimm M,Reuter S,Vieira RP,Ayata K,Cicko S,Sorichter S,Walther DJ,Virchow JC,Taube C,Idzko M

doi

10.1164/rccm.201208-1440OC

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

476-85

issue

5

eissn

1073-449X

issn

1535-4970

pii

rccm.201208-1440OC

journal_volume

187

pub_type

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