Histamine receptor 2 modifies iNKT cell activity within the inflamed lung.

Abstract

Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H₂ R). The aim of this study was to determine the role of H₂ R in modulating lung inflammatory responses. H₂ 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. H₂ R-deficient animals and CD1d/H₂ R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGalCer or OCH) to invariant natural killer T (iNKT) cells. 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 H₂ R-deficient animals. Flow cytometric analysis of lung tissue from H₂ R-deficient animals revealed increased numbers of CD1d⁺ dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer-stimulated iNKT cells from H₂ 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 H₂ R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H₂ R-deficient (CD1d^-/- H₂ R^-/- ) animals normalized the lung response to HDM. The deliberate activation of H₂ R, 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.