Our group has been pursuing the studies of the interactions between chemoattractants and their receptors.We are especially interested in the role of formylpeptide receptors in host defense and proinflammatory responses, as well as their ability to indirectly interact with chemokine receptors that also act as HIV-1 co-receptors. In humans, there are three functional fMLF receptors, the high affinity FPR, its low affinity variant FPRL1, and a third receptor FPRL2 that does not respond to fMLF but has been shown to share some synthetic peptide agonists with FPRL1. Mice with disrupted FPR gene have a normal phenotype but reduced resistance to bacterial infection, suggesting this receptor may be involved in host defense against microbial invasion. Recently our laboratory and other laboratories identified a number of novel chemotactic agonists for both FPR and FPRL1. These agonists include small peptides derived from peptide libraries, peptide domains derived from HIV-1 envelope proteins, and more importantly several host-derived agonists linked to inflammatory and neurodegenerative diseases. We therefore postulate that the functional scope of formylpeptide receptors may be much broader than initially thought based on their potential participation in endogenous patho-physiological processes. We have identified additional host derived polypeptides that act as potential agonists for formylpeptide receptors. The neutrophil granule protein Cathepsin G (CaG) is bactericidal, cleaves a number of proteins, promotes antibody responses when injected in mice, and chemoattracts human granulocytes and monocytes. Several lines of evidence suggest that CaG uses the prototype formylpeptide receptor FPR for its chemotactic activity. CaG also exhibits some unique properties in interacting with FPR. We plan to further clarify whether CaG as a serine protease might cleave FPR or other cell surface molecules to yield de facto agonists for FPR and to identify the domains in CaG and in FPR that are involved in receptor/ligand interaction. In studies of the signaling pathways coupled to formylpeptide receptors, we found that these two receptors when activated by their agonists are capable of desensitizing chemokine receptors CCR5 and CXCR4, which also serve as essential coreceptors for HIV-1. By desensitizing CCR5 and CXCR4, formylpetide receptor agonists inhibited HIV-1 fusion and replication in primary mononuclear cells and cell lines transfected to express formylpeptide receptors and HIV coreceptors. These results prompted us to further define the key elements in the signaling cascade that are responsible for the desensitizing effects of activated formylpeptide receptors. We also suggested the use of coreceptor desensitization strategy as additional, complementary anti-HIV -1 therapy.We have revealed a potentially important role of FPRL1 in the inflammation and neurodegeneration in Alzheimer's disease, which is characterized by the over-production of Ab42 in the brain in association with macrophage (microglia) accumulation and activation. FPRL1 has not only been found to mediate the chemotactic activity of Ab42 but also promote its internalization and subsequent intracellular aggregation in macrophages. The interaction of FPRL1 with Ab42, but not with non-amyloidogenic peptide agonists, resulted in increased apoptosis of the cells. The mouse counterpart of FPRL1 named mFPR2 was also found to mediate chemotaxis and super oxide release in myeloid cell stimulated by Ab42 and the expression of this receptor was enhanced in microglial cells of newborn mice stimulated with proinflammatory signals. These findings provide the rationale for our proposed studies using mouse models of Alzheimer's disease to further elucidate the contribution of FPRL1 and mFPR2 to the pathogenesis of Alzheimer's disease. Unexpectedly, we found that a peptide fragment of the human prion, which is detectable in the CNS of patients with prion disease, is also a chemotactic agonist for FPRL1, suggesting the possible involvement of this receptor in inflammatory responses seen in prion diseases. Despite the progressive neurodegenration in AD, the occipital lobes of the patient brains are rarely affected. This has led to the identification of a gene coding for a small neuroprotective polypeptide Humanin (HN). In studies of the mechanisms of HN in neuroprotection, we found that HN shares the formylpeptide receptor FPRL1 with Ab42. We also obtained evidence to suggest that by sharing FPRL1, HN reduces the aggregation of Ab42 in macrophages and its toxicity for neuronal cells.
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