The dendritic cell mannose receptor mediates allergen internalization and maturation involving notch 1 signalling

Abstract

Summary Dendritic cells (DCs) have been shown recently to play a key role in inducing and mediating T helper type 2 (Th2) responses associated with atopic disease. These responses are mediated in part by ligation to different Toll-like receptors (TLRs) and C-type lectins, e.g. the mannose receptor (MR), depending upon the DC subset involved and the respective microenvironments. Because ovalbumin (OVA) (which is structurally related to various allergens) can engage the MR, we can use OVA stimulation as a model for understanding the roles of both TLRs and the MR in allergic inflammatory responses. We examined TLR- and MR-mediated responses from mouse bone marrow-derived DCs in the context of antigen recognition and presentation in addition to examining the relationship between notch 1, TLRs and MR signalling pathways. This work demonstrated that OVA-mediated signalling up-regulated both TLR-2 and MR and that MR RNA interference (RNAi) but not TLR2 RNAi inhibited DC internalization of fluorescein isothiocyanate–OVA. Furthermore, MR RNAi inhibited OVA- and house dust mite allergen extract-induced DC maturation and MR RNAi and TLR2 RNAi influenced DC interleukin-12 production independently. Finally, we demonstrated that blocking notch 1 signalling inhibited both notch 1 and TLR-2 expression but not MR expression levels. However, MR RNAi inhibited the expression of MR, TLR-2 and notch 1. These results indicate that MR is the primary receptor mediating the internalization of environmental allergen glycoproteins. In addition, TLR-2 and notch 1 play important roles in DC maturation and antigen presentation and signals originating from the MR and TLR-2 receptors converge with the notch 1 signalling pathway.