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Histamine receptor 2 modifies iNKT cell activity within the inflamed lung
Author(s) -
Ferstl R.,
Frei R.,
Barcik W.,
Schiavi E.,
Wanke K.,
Ziegler M.,
RodriguezPerez N.,
Groeger D.,
Konieczna P.,
Zeiter S.,
Nehrbass D.,
Lauener R.,
Akdis C.A.,
O'Mahony L.
Publication year - 2017
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.13227
Subject(s) - dimaprit , immunology , cd1d , histamine , proinflammatory cytokine , plasmacytoid dendritic cell , allergic inflammation , medicine , dendritic cell , biology , t cell , receptor , inflammation , natural killer t cell , antigen , histamine receptor , endocrinology , immune system , antagonist
Background Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H 2 R). The aim of this study was to determine the role of H 2 R in modulating lung inflammatory responses. Methods H 2 R was blocked using famotidine or activated using dimaprit in both the ovalbumin ( OVA ) and house dust mite extract ( HDM ) murine models of respiratory inflammation. H 2 R‐deficient animals and CD 1d/H 2 R‐deficient animals were utilized to examine the CD 1d presentation of lipid antigens (αGalCer or OCH ) to invariant natural killer T ( iNKT ) cells. Results Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM ‐induced airway diseases were more severe in H 2 R‐deficient animals. Flow cytometric analysis of lung tissue from H 2 R‐deficient animals revealed increased numbers of CD 1d + dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer‐stimulated iNKT cells from H 2 R‐deficient mice secreted higher levels of IL ‐4, IL ‐5, and GM ‐ CSF . In vivo, αGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H 2 R‐deficient or famotidine‐treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H 2 R‐deficient ( CD 1d −/− H 2 R −/− ) animals normalized the lung response to HDM. Conclusion The deliberate activation of H 2 R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD 1d‐mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.