The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine.Objective
We sought to identify the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling.Methods
Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H2R)–deficient mice, histamine receptors, and their signaling pathways were investigated.Results
Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and TH1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H2R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus, which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H2R-deficient animals.Conclusion
Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H2R.