TLR8 and NOD signaling synergistically induce the production of IL-1β and IL-23 in monocyte-derived DCs and enhance the expression of the feedback inhibitor SOCS2

Pattern recognition receptors (PRRs) like Toll-like receptors (TLRs) and NOD-like receptors (NLRs) are important sensors of microbial products. Although they are referred to as innate immune receptors, they make essential contributions to adaptive immune responses by activating dendritic cells (DCs). Simultaneous activation of DCs via different classes of PRRs provides a powerful tool for inducing strong immune responses. In the present study we investigate the interplay of the NLRs NOD1 and NOD2 and their crosstalk with TLR signaling in terms of DC-activation. We found strong synergistic effects upon treatment with NOD1 and NOD2 ligands combined with the TLR7/8 agonist R848. Simultaneous stimulation of monocyte-derived DCs resulted in highly increased production of IL-1β, IL-23 and SOCS2, a member of the suppressor of cytokine signaling (SOCS) family. Silencing of SOCS2 resulted in enhanced IL-23 expression, indicating that SOCS2 is involved in the regulation of TLR/NOD-dependent cytokine secretion. Finally, we demonstrate that TLR7/8-, NOD1- and NOD2-activated DCs promote CD4+ T cells to release increased amounts of IL-17. These results demonstrate that cooperative activation of DCs with NOD1 and NOD2 agonists and TLR7/8 ligands results in a synergistic release of pro-inflammatory mediators which promote the activation of IL-17-producing T cells.