Increased translocation of antigens to endosomes and TLR4 mediated endosomal recruitment of TAP contribute to nicotine augmented cross-presentation

Abstract

Cross-presentation by dendritic cells (DCs) requires surface molecules such as lectin, CD40, langerin, heat shock protein, mannose receptor, mediated endocytosis, the endosomal translocation of internalized antigen, and the relocation of transporter associated with antigen processing (TAP). Although the activation of α7 nicotinic acetylcholine receptor (α7 nAchR) up-regulate surface molecule expression, augment endocytosis, and enhance cross-presentation, the molecular mechanism of α7 nAchR activation-increased cross-presentation is still poorly understood. In this study, we investigated the role of mannose receptor in nicotine-increased cross-presentation and the mechanism that endotoxins orchestrating the recruitment of TAP toward endosomes. We demonstrated that nicotine increase the expressiones of mannose receptor and Toll-like receptor 4 (TLR4) via PI3K-Akt-mTOR-p70S6 pathway. Both endosomal translocation of mannose receptor-internalized antigens and TLR4 sig- naling are necessary for nicotine-augmented cross-presentation and cross-priming. Importantly, the recruitment of TAP toward endosomes via TLR4-MyD88-IRAK4 signaling contributes to nicotine-increased cross-presentation and cross-activation of T cells. Thus, these data suggest that increased recruitment of TAP to Ag-containing vesicles contributes to the superior cross-presentation efficacy of α7 nAchR activated DCs.

PYR-41 and Thalidomide Impair Dendritic Cell Cross-Presentation by Inhibiting Myddosome Formation and Attenuating the Endosomal Recruitments of p97 and Sec61 via NF-κB Inactivation

“…Our previous study showed that TLR4-MyD88-IRAK4-dependent TAP translocation from endoplasmic reticulum toward endosomes facilitates DC cross-presentation [ 18 ]. Other reports also demonstrated that the endosomal recruitment of Sec61, which depends on NF- κ B activation, is responsible for cross-presentation [ 15 ].…”

“…TLR4, as an essential signal pathway of pattern recognition receptor, could be internalized by LPS-stimulated cells and promote myddosome formation, which facilitate the endosomal recruitments of TAP and Sec61 [ 15 , 18 , 20 , 21 ]. As PYR-41 and thalidomide inhibited the endosomal recruitments of p97/Sec61 (Figures 5 – 7 ) and attenuated NF- κ B activation ( Figure 8 ), we wonder whether PYR-41- impaired cross-presentation and thalidomide-impaired cross-presentation were due to the inhibition of myddosome formation.…”

“…This process is of particular importance, because it permits the presentation of exogenous antigens, which are normally presented by MHC II on the surface of infected DC [ 9 ]. In our previous studies, ovalbumin was used to pulse DC and revealed that α 7 nAChR activation increases DC cross-presentation [ 18 , 24 ]. SIINFEKL peptide, which corresponds to ovalbumin 257-264 and directly binds to MHC class I molecules, is an intracellular model antigen for the MHC I presentation pathway [ 29 ].…”

“…On the other hand, NF- κ B activation-dependent endosomal relocation of Sec6 was also documented to be needed for DC cross-presentation [ 15 ]. Our previous study further revealed that the endosomal TAP relocation depends on TLR4-MyD88-IRAK4 signaling [ 18 ]. Hence, despite that NF- κ B inactivation-decreased myddosome formation and the inhibition of endosomal recruitment of p97/Sec61 were verified to contribute to PYR-41- and thalidomide-impaired cross-presentation, the exact effects of PYR-41 and thalidomide on the endosomal recruitment of TAP are still uncertain and need further explorations.…”

“…Toll-like receptor 4 (TLR4) signaling, which mediates the recruitment of myeloid differentiation factor 88 (MyD88) and results in I κ B kinase degradation, was found to play a vital role in cross-presentation [ 15 , 17 – 19 ]. For example, TLR4-MyD88 signaling mediated the endosomal relocation of transporter associated with antigen processing (TAP) and Sec61 to allow the entry of antigenic peptides [ 15 , 17 , 18 ]. Upon activation, MyD88 and IRAK4 were recruited to the endosomes to form myddosome (TLR4-MyD88-IRAK4) [ 20 , 21 ].…”