FcRγ-chain, Grb2 and SHP-1 are invovled in mannose receptor (CD206)-mediated signaling in relation to tuberculosis (INC4P.329)

Abstract

Abstract The mannose receptor (MR, CD206) is highly expressed on human macrophages. It is a major pattern recognition receptor for pathogens, mediates phagocytosis and endocytosis, and regulates inflammatory signaling pathways. We have shown that the MR mediates Mycobacterium tuberculosis (M.tb) phagocytosis by human macrophages which leads to up-regulation of PPARγ expression and a delay in phagosome-lysosome (P-L) fusion. However, the associated receptor-specific downstream signaling molecules are unknown. We assayed for MR-associated proteins by MALDI-TOF and Western blot using a pull down assay with macrophage lysates and phosphorylated and un-phosphorylated MR cytoplasmic tail peptides. We have identified that FcRg-chain interacts with the MR and this interaction is necessary for MR surface exposure on human monocyte-derived macrophages (MDMs). Furthermore, M.tb infection of MDMs leads to phosphorylation of MR tyrosine residues and recruitment of Grb2 which initiates the Rac/Pak/Cdc-42 signaling cascade required for phagocytosis, and activation of MAP kinases and the PI3k/Akt pathway. MR activation also recruits and activates SHP-1. SHP-1 blockade increases M.tb P-L fusion and inflammatory cytokines. In conclusion, we have identified key MR signaling molecules and regulatory pathways which initiate phagocytosis and other immune-related functions in human macrophages.