Histamine receptor 2 modifies iNKT cell activity within the inflamed lung

BackgroundHistamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2R). The aim of this study was to determine the role of H2R in modulating lung inflammatory responses. MethodsH(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. H2R-deficient animals and CD1d/H2R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (GalCer or OCH) to invariant natural killer T (iNKT) cells. ResultsFamotidine 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 H2R-deficient animals. Flow cytometric analysis of lung tissue from H2R-deficient animals revealed increased numbers of CD1d(+) dendritic cells and increased numbers of iNKT cells. In vitro, GalCer-stimulated iNKT cells from H2R-deficient mice secreted higher levels of IL-4, IL-5, and GM-CSF. In vivo, GalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H2R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to GalCer. Removal of iNKT cells in H2R-deficient (CD1d(-/-)H(2)R(-/-)) animals normalized the lung response to HDM. ConclusionThe deliberate activation of H2R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.