Plasmacytoid dendritic cells (pDC) are the first line of host defense and link innate to adaptive immunity. These immune cells are activated after recognition of pathogen by sensors like Toll-like receptors (TLR). TLR activation triggers production of type I interferon and proinflammatory cytokines. However, prolonged pDC activation and consequently massive type I interferon production may have adverse effects in the chronic phase of infections and auto-immune diseases. Therefore, modulating pDC function and understanding the mechanisms underlying this pDC regulation is of great clinical interest. Only two studies showed that a natural molecule, histamine, strongly inhibits IFN production by Influenza-activated pDC and by activated pDC from psoriasis patients.
Human pDC were purified from healthy donors and cultivated in presence of virus overnight. IFN-a production by pDC was quantified by ELISA and relative mRNA levels of different interferons, interferon-stimulating genes and pro-inflammatory cytokines were measured by RT-qPCR. We tested natural (histamine, spermine, serotonine) and synthetic amines on pDC activated by HIV. siRNA was performed successfully for the first time on primary human pDC to evaluate the implication of the proteins of interest. 29S8 mice were infected by inhalation with influenza in presence or not of the amines and IFN levels in broncho-alveolar fluids were measured.
We show that amines inhibit IFN-I production and ISG by stimulated pDC. Furthermore, IFN production was fully inhibited in a mouse model of influenza infection. Surprisingly, histamine receptors are not required for pDC inhibition. We show that the positive ammonium moiety is essential for the inhibitory activity and we identify CXCR4 as the unexpected common link between amine effect and pDC inhibition.
Our study establishes a functional link between natural amines and the innate immune system and identifies CXCR4 as a potential ‘on-off’ switch of pDC activity and therefore as a promising therapeutic target in chronic diseases.