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DOI: 10.1055/s-0032-1329793
Platelet serotonin drives allergic airway inflammation
Rationale: Serotonin (5-hydroyxtryptamine, 5-HT) appears to be involved in the pathogenesis of allergic airway inflammation (AAI). It is not known however how 5-HT may enhance AAI.
Objective: To investigate production and release of 5-HT in asthma.
Methods: Tryptophan hydroxylase (TPH) 1-deficient and parachlorophenylalanine- (5-HT-synthesis inhibitor) treated animals were challenged in OVA-alum and HDM-models of AAI. Experiments with bone-marrow chimera, mast cell-deficient animals, platelet transfusion, and a bone marrow dendritic cells (BMDC)-driven model of AAI were performed. 5-HT-levels in bronchoalveolar lavage fluid (BALF) and serum of animals with AAI and patients with asthma were measured.
Results: 5-HT-levels were increased in BALF of mice and human asthmatics following allergen provocation. TPH1-deficiency and TPH1-inhibition reduced BAL-eosinophilia, Th2-cytokine production, and bronchial hyperresponsiveness in 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 BM-chimera experiments. Experiments in mast cell-deficient mice revealed mast cells not to be the source of 5-HT. In contrast, transfusion of platelets from WT and TPH1-deficient mice revealed that only platelets containing 5-HT enhanced AAI. BMDC from TPH1-deficient mice had a reduced capacity to prime for Th2-immuity in vitro and in vivo.
Conclusion: In summary, genetic or pharmacological inhibition of TPH1 reduced AAI. Platelet, not mast cell serotonin enhanced AAI and may be essential for Th2-priming by DCs, a mechanism that could offer novel therapeutic options in asthma.