Histamine Receptor 2 Modifies iNKT Cell Activity within the Inflamed Lung

Abstract

Background

Histamine 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.

Methods

H₂R 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 (αGal-Cer 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 disease 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, αGal-Cer-stimulated iNKT cells from H₂R-deficient mice secreted higher levels of IL-4, IL-5 and GM-CSF. In vivo, αGal-Cer 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 αGalCer. Removal of iNKT cells in H₂R-deficient (CD1d^-/-H₂R^-/-) animals normalized the lung response to HDM.

Conclusion

The 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 are contributing to the pathology.

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