Histamine Activates Human Eosinophils via H2R and H4R Predominantly in Atopic Dermatitis Patients

Abstract

Atopic dermatitis (AD) is maintained by a variety of cells and inflammatory mediators, including eosinophils and histamine. We recently reported that eosinophils from AD patients highly express the H4R. However, its immunomodulatory function in eosinophils is still largely unexplored. In this study, transcriptome analysis of blood eosinophils from AD patients stimulated with histamine and the H4R agonist ST-1006 revealed several regulated genes (e.g., IL-18R, IL-1RL1, PDE4B, CXCR4) involved in inflammation. Subsequently, the impact of histamine on one of the strongly regulated genes, the IL-18 receptor (IL-18Rα), was investigated in detail. Stimulation with histamine induced the upregulation of IL-18Rα at mRNA and at the protein level in human eosinophils, which was more pronounced in cells from AD patients than in cells from healthy controls. IL-18 was upregulated via histamine as well. After pre-incubation with histamine and IFN-γ, subsequent stimulation with IL-18 resulted in an increased ECP mRNA expression. The activation of eosinophils by histamine, in combination with IFN-γ and IL-5, was also accompanied by an upregulation of CD69. Thus, our results indicate a crucial role of histamine in the upregulation of the IL-18/IL-18R axis and in the activation of human eosinophils from AD patients.

The stimulation of TH2 cells results in increased IL‐5 and IL‐13 production via the H4 receptor

“…[31][32][33] Furthermore an upregulation of IL-18 expression and its cognate receptor IL-18Rα was shown to be induced via H 2 -and H 4 -receptor in human eosinophils. 34 Altogether, these inspiring data demonstrate the significance of H 4 receptor in the regulation of several immune responses.…”

“…Furthermore an upregulation of IL‐18 expression and its cognate receptor IL‐18Rα was shown to be induced via H 2 ‐ and H 4 ‐receptor in human eosinophils 34 …”

Biomarkers of atopic dermatitis: a meta-analysis over the last decade

“…At the site of in ammation, eosinophils come into contact with histamine, which is mostly released from activated mast cells and basophils, resulting in strongly elevated levels of this bioamine in the skin of AD patients [21]. Eosinophils can be used as antigen presenting cells and Th-secreting cell chemokines to participate in obtaining immune responses, and can also be used as main effector cells to mediate tissue damage and functional disorders by releasing toxic particles and mitochondrial DNA [22].…”

The causal relationship and potential mediators between plasma lipids and atopic dermatitis: a bidirectional two-sample, two-step mendelian randomization

“…Research by Beyer et al has shown that histamine and IFN-γ can synergistically upregulate the expression of IL-18R1 in eosinophils of AD patients. This promotive effect on IL-18R1 expression could lead to an increase in the expression of the eosinophil granule proteins [ 39 ]. Although in our study, only IL-18R1 was found to mediate the effect of plasma lipids on AD risk, part of our results indicates a significant correlation between plasma lipids and circulating inflammatory protein levels.…”