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.

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 (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 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, αGalCer‐stimulated iNKT cells from H₂R‐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 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.

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 is contributing to the pathology.