Comparative genomics identified TLR-dependent fine tuning of the dendritic cell immune response by melatonin

Abstract Melatonin, a neuro hormone, has been shown to activate human monocytes and induce their cytotoxic properties in addition to the production of IL-1, IL-6, and TNF-α. The molecular mechanisms involved in melatonin and dendritic cell interactions are largely unknown. In this study, we performed a comprehensive RNA sequencing (RNA-seq)-based analysis of monocyte-derived human dendritic cells across different melatonin stimulations. We profiled gene expression changes among naïve DCs along with DCs generated with melatonin (MDCs) and DCs matured with melatonin (DCMs). We found that melatonin significantly promoted the morphological maturation of MDCs and increased the expression of DC-related surface markers. Furthermore, MDCs increased the general immune response by promoting the secretion of IL-12, IL-6 and IFN-γ cytokines and enhancing the proliferation of TH cells, while DCM did not. Genome-wide comparative transcriptomic profiling showed that the expression of 7417 genes was significantly upregulated, and 3325 genes were significantly downregulated in MDCs. We observed the spatiotemporal activity of TLR 2-, 4-, 6- and 8-specific genes in MDCs. Interestingly, we found that the expression of TLR 10-specific signaling genes was significantly higher in DCMs. Further in vitro validation showed that along with TLRs, the upregulation of IRAK, GRB2, CREB and TNFRSF was significantly associated with MDCs. Overall, we found that during the differentiation of dendritic cells, the presence of melatonin generates a unique population of dendritic cells with activated TLR4 signaling. DCs generated through this unique culture process may act as good candidates for immunomodulation during cancer and inflammation. Supported by grants fromDST-SERB, GOI (CRG/2019/001296)