Figure 1.

The role of histamine H₄ receptors on human cells relevant in AD. These receptors (H4R) are expressed on keratinocytes and different immune cell populations, which play a role in inflamed skin of AD. In the Th2‐dominated phase of acute inflammation, various cell types such as mast cells, granulocytes, Th cells, macrophages and APCs are detectable in the skin. Engagement of the FcεRI triggers release of histamine from mast cells and basophils. Histamine in turn is able to mediate several pro‐inflammatory and anti‐inflammatory effects via its binding to H₄ receptors. In basophils, stimulation of H₄ receptors reduces the FcεRI cross‐linking‐mediated release of sulfidoleukotrienes. In APCs, various pro‐inflammatory cytokines like IL‐12, IL‐27 and CCL2 are down‐regulated. However, the decrease of these cytokines results to an impaired Th1 polarization and to a shift towards a Th2‐driven immune response, which further can lead to an exacerbation of the symptoms seen in acute AD. In line with this, histamine via H₄ receptors increases the chemotaxis of APCs, eosinophils and basophils that is essential for the recruitment of the cells into the skin. Moreover, stimulation of H₄ receptors up‐regulates the production of IL‐31 in Th2 cells and TSLP release from keratinocytes. IL‐31 and TSLP are able to trigger a Th2 polarization and to directly mediate pruritus. In addition, histamine through H₄ receptors increases the proliferation rate in keratinocytes of AD patients. Conclusively, the pro‐inflammatory effects of H₄ receptors seem to be more important in disease pathology. The effects mediated by H₄ receptors are highlighted in red.