Role of Formylpeptide Receptors in Host Defense

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We have identified a G-protein coupled receptor FPRL1 used by A42 peptides to induce human macrophage chemotaxis and activation. FPRL1 was originally defined as a low-affinity receptor for the bacterial chemotactic formylated peptde fMLF and is also shared by a variety of exogenous and host-derived chemotactic polypeptides. We additionally found that upon binding to FPRL1, A42 and FPRL1 complexes were internalized into the cytoplasmic compartment of human macrophages and prolonged exposure to A42 resulted in the retention of A42/FPRL1 complexes in the cells, followed by formation of Congo-red positive fibrils. In contrast, although brief exposure of macrophages to A42 peptides also resulted in A42 peptide ingestion, there was no formation of fibrillary aggregation, suggesting a lower burden of A42 peptides could be degraded by macrophages. In microglial cells isolated from new born mice, treatment with a variety of proinflammatory agents such as the ligands for the Toll like receptors (TLRs), TNF?, IFN? and CD40 increases the expression of mFPR2, a mouse counterpart of human FPRL1. Activated mouse microglial cells exhibited potent chemotactic activity to A42 peptides and ingest the peptides through the receptor mFPR2. Our observations suggest that FPRL1 and its mouse counterpart may act as a sensor in the CNS for over produced A42 peptides in AD, and mediate inflammatory responses and for the processing of A42 peptides, which may determine the rate of the progression of AD pathology. To more precisely evaluate the role of FPRL1 (mFPR2) in innate host defense, inflammation and in the pathogenesis of AD, we have generated a mouse strain depleted of mFPR2. Our ongoing studies have revealed that in a mouse model of AD, depletion of mFPR2 reduced the number of activated microglial cells in the brain in association with increased level of A42 peptide deposition. Thus, FPRL1 (mFPR2) appears to play an important role in host defense against the accumulation and aggregation of A42 peptides in AD. mFPR2-/- mice also provide us with a unique tool to study the role of this receptor in other proinflammtory and immune diseases as well as in the development of cancer. We found that in an ovalbumin (OVA)-induced inflammatory and immune response model, as compared with wild type mice, mFPR2-/- showed markedly reduced leukocyte infiltration in the lung tissue and in the bronchial lumen, in association with reduce anti-body responses to OVA. Thus our studies suggest a key role of mFPR2 in inflammatory and immune responses to foreign antigen. Further studies are underway to determine the role of mFPR2 in inflammatory bowel disease-induced colon cancer and in metastasis of mouse lung cancer and melanoma.