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Activated N-formyl peptide receptor and high-affinity IgE receptor occupy common domains for signaling and internalization.

ABSTRACT: Immune cells display multiple cell surface receptors that integrate signals for survival, proliferation, migration, and degranulation. Here, immunogold labeling is used to map the plasma membrane distributions of two separate receptors, the N-formyl peptide receptor (FPR) and the high-affinity IgE receptor (FepsilonRI). We show that the FPR forms signaling clusters in response to monovalent ligand. These domains recruit Gi, followed by the negative regulatory molecule arrestin2. There are low levels of colocalization of FPR with FcepsilonRI in unstimulated cells, shown by computer simulation to be a consequence of receptor density. Remarkably, there is a large increase in receptor coclustering when cells are simultaneously treated with N-formyl-methionyl-leucyl-phenylalanine and IgE plus polyvalent antigen. The proximity of two active receptors may promote localized cross-talk, leading to enhanced inositol-(3,4,5)-trisphosphate production and secretion. Some cointernalization and trafficking of the two receptors can be detected by live cell imaging, but the bulk of FPR and FcepsilonRI segregates over time. This segregation is associated with more efficient internalization of cross-linked FcepsilonRI than of arrestin-desensitized FPR. The observation of receptors in lightly coated membrane invaginations suggests that, despite the lack of caveolin, hematopoietic cells harbor caveolae-like structures that are candidates for nonclathrin-mediated endocytosis.

SUBMITTER: Xue M

PROVIDER: S-EPMC1838997 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Crosslinking of receptor-bound Immunoglobulin E (IgE) triggers immediate hypersensitivity reactions including anaphylaxis. Blocking the interaction of IgE with its high-affinity receptor, Fc?RI, on mast cells and basophils is an attractive strategy for the treatment of allergies. This approach has seen clinical success using the anti-IgE monoclonal antibody, omalizumab. We recently designed and characterized a novel Fc?RI-mimetic peptide (PepE) which contains the two key Fc?RI ?-chain receptor loops known to interact with the ?-heavy chain of IgE, C'-E and B-C, with an optimized linker for joining them. PepE has high specificity and affinity for IgE, blocks IgE binding to Fc?RI and prevents IgE-induced mediator release from RBL2H3 cells. We have now investigated the biological effects of this peptide in vivo using a line of mice (BALB/c Il4raF709) very sensitive to IgE-mediated systemic anaphylaxis. IgE-deficient (IgE-/-) Il4raF709 mice were passively sensitized with the anti-DNP IgE monoclonal antibody (SPE-7) and subsequently challenged i.v. with DNP-BSA. Mice receiving a single dose of PepE prior to sensitization with SPE-7 IgE were fully protected from anaphylaxis while vehicle control-treated mice displayed strong reactions with significant core body temperature drops and elevated levels of mouse mast cell protease-1 (mMCP-1) in the serum. However, PepE had no effect on IgE-mediated anaphylaxis if given after IgE administration in IgE-/- mice, suggesting that PepE can block binding of free IgE to Fc?RI but cannot compete with the receptor for already bound IgE in vivo. A single dose of PepE treatment did not protect IgE sufficient mice from IgE mediated anaphylaxis. However, a 3 week long course of PepE treatment protected IgE sufficient Il4raF709 mice from body temperature drops and elevation of serum mMCP-1. Our findings establish the potential of this type of structure for blocking IgE binding to mast cells in vivo and suggest that related peptides might have the potential to attenuate clinical allergic reactions.

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Activated N-formyl peptide receptor and high-affinity IgE receptor occupy common domains for signaling and internalization.

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