uPAR another newly discovered ligand

uPAR, another newly discovered ligand, has implicated FPRL1 as a potential link between the fibrinolytic cascade and inflammation. uPA is a serine protease best known for its ability to regulate fibrinolysis and for its importance in tissue remodeling and tumor invasion [49]. However, uPA also induces leukocyte chemotaxis in vitro and is required for leukocyte trafficking to sites of inflammation in vivo[50]. The mechanism involves indirect activation of FPRL1 through the liberation of a chemotactic peptide, D2D388–274, from uPAR (CD87) [51]. Also, the presence of both uPAR and FPRL1 on the cell surface is required for the chemotactic activity of uPA, whereas FPRL1 alone is sufficient for the effect of D2D388–274[51]. Thus, uPAR might facilitate fibrinolysis as well as being a source of chemotactic proinflammatory peptides necessary for host defense.
Role of FPRL1 in amyloidogenic diseases Interest in the potential role of FPRL1 in amyloidogenic diseases originated from the discovery that at least three polypeptides associated with these diseases are specific chemotactic agonists for FPRL1. These polypeptides are serum amyloid A (SAA) [52], a 42 amino-acid form of β amyloid peptide (Aβ42) [53] and a peptide fragment of the aberrant human prion protein [54]. SAA is an acute-phase protein, and under chronic or recurrent inflammatory conditions elevated SAA might form reactive amyloidosis in peripheral tissues resulting in progressive loss of organ function. During the amyloidogenic process, SAA can be enzymatically cleaved into fragments to form amorphous amyloid fibril deposits [55]. Because monocytes and/or macrophages are the source of SAA cleaving enzymes and these Guanethidine Sulfate accumulate at the sites of amyloid deposits, the usage of FPRL1 by SAA to chemoattract phagocytic leukocytes could recruit phagocytes to promote SAA degradation and clearance. However, cell activation as a result of SAA–FPRL1 interactions could also exacerbate local inflammatory responses and tissue injury. Consequently, it remains to be determined whether FPRL1-mediated cell responses to SAA occur in vivo and, if so, whether they are beneficial or detrimental to the host. Aβ42 is an enzymatic cleavage fragment of the amyloid precursor protein (APP) and its aggregated form is a major component of the senile plaques seen in the brain tissue of patients suffering from AD. Chronic inflammation is associated with Aβ deposition (reviewed in [56]). Moreover, in AD patients, nonsteroidal anti-inflammatory drugs (NSAIDs) can retard disease progression and significantly reduce the number of plaque-associated reactive microglial cells [57]. In vitro, Aβ42 and its shorter peptide fragments activate microglia and monocytes by increasing cell adhesion, chemotaxis, phagocytosis and the production of neurotoxic and proinflammatory mediators, which can be inhibited by NSAIDs 10., 56.. The relevance of FPRL1 to the proinflammatory aspects of AD is suggested because FPRL1 is a chemotactic receptor for Aβ42, which induces monocyte migration and activation [53]. Other Aβ receptors 8., 56. have been reported, although only FPRL1 is a GPCR capable of generating both chemotactic and activating signals. In brain tissues of AD patients, high level expression of FPRL1 mRNA was detected in CD11b+ mononuclear phagocytes that surround or infiltrate the plaques [53]. Human Aβ42 also chemoattracts and activates murine microglia apparently through the use of FPR2, the FPRL1 homologue 58., 59.. This finding will enable experimental investigation of the role of FPRL1 in murine models of AD. FPRL1 also can promote the cellular uptake of Aβ42[60] by rapidly internalizing it into the cytoplasmic compartment in the form of Aβ42–FPRL1 complexes. Persistent exposure to Aβ42 results in the intracellular retention of Aβ42–FPRL1 complexes and the formation of Congo-red positive fibrils in mononuclear phagocytes. Thus, FPRL1 might not only account for Aβ42 induced recruitment and activation of mononuclear phagocytes in senile plaques, but might also participate actively in Aβ42 uptake and the resultant fibrillar formation in AD.