Structure and Function of Leukocyte Chemoattractant Receptors

Ye, Richard D.; Boulay, F.

doi:10.1016/s1054-3589(08)60073-3

Cited by 101 publications

(88 citation statements)

References 321 publications

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“…The first identified and most investigated FPR ligands, the N-formylated peptides, originate from exogenous sources such as the proteins of invading pathogens and have been shown to be powerful attractants for mammalian phagocytes to infected tissue. The two other human N-formyl peptide receptors, FPRL1 and FPRL2, share 69% and 56% amino acid identity with FPR, respectively [3]. FPRL1 and FPR are expressed in phagocytic cells and also in other cell types including hepatocytes, dendritic cells and cells of the nervous system [11,13].…”

Section: Discussionmentioning

confidence: 99%

“…Since the identification and molecular cloning of the N-formyl peptide receptor [2] and its homologues [1,3] a decade ago, their pathophysiological role has broaded beyond host resistance against exogenous pathogens. In particular, the usage of FPRL1 and FPRL2 by hostderived agonists suggests that these receptors may play a crucial role in the regulation of the inflammatory processes associated with tissue damage and neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Like other chemoattractants, including the activated complement component 5 (C5a), platelet-activating factor (PAF), leukotriene B4 (LTB4) and a superfamily of chemokines, they activate seven-transmembranedomain Gi protein-coupled receptors (GPCR) [1][2][3] present on phagocytic cells and other cell types. The binding of chemoattractants to their receptors on phagocytic cells causes calcium mobilization, activation of the NADPH oxidase, and the release of the content of granules.…”

Section: Introductionmentioning

confidence: 99%

“…The first ligand shown to bind with high affinity (low nanomolar range) to this receptor was lipoxin A4 (LXA4), an anti-inflammatory lipid mediator [10]. Recently, FPRL1 has emerged as a promiscuous receptor, also activated by the pathogenderived peptide Hp (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) from Helicobacter pylori, by host-derived proteins and peptides such as Ac1-25 from annexin 1, cathelicidin LL37, a fragment of the urokinase receptor, the serum amyloid A, the amyloid b peptide (Ab42), the prion protein fragment PrP(106-126), the neuroprotective peptide humanin, and by different synthetic peptides including the hexapeptide Trp-LysTyr-Met-Val-D-Met-NH 2 (WKYMVm) [11,12]. FPRL2 does not respond to fMLF [13], but instead is activated by some non-formylated chemotactic peptides identified as agonists for FPRL1 [14,15].…”

Section: Introductionmentioning

confidence: 99%

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Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, and can attract leukocytes to sites of infection or tissue damage. In this study, HL-60 cell lines expressing the human N-formyl peptide receptor FPR or its two homologues (FPRL1, FPRL2) were used to determine the receptor selectivity of N-formylated peptides derived from Listeria monocytogenes or from human mitochondrial proteins. Bacterial peptides were 100-fold more potent on FPR than on FPRL1, whereas none of them could trigger intracellular signaling through FPRL2. In contrast, N-formylated hexapeptides corresponding to the N terminus of mitochondrial NADH dehydrogenase subunits 4 (fMLKLIV) and 6 (fMMYALF), and cytochrome c oxidase subunit I (fMFADRW) were equally potent on FPR and FPRL1. They triggered cellular responses with the following order of potency: fMMYALF > fMLKLIV > fMFADRW, with an EC 50 , in a Fura-2 calcium mobilization assay, of 10 nM, 44 nM, and 160 nM on FPRexpressing cells, and 15 nM, 55 nM and 120 nM on FPRL1-expressing cells. fMMYALF was also a low-affinity agonist of FPRL2 (EC 50 of 1 lM) and was chemotactic for both FPRL1-and FPRL2-expressing cells. We identified novel mitochondrial host-derived agonists for human N-formyl-peptide receptors that might play a role in inflammatory or degenerative processes linked to their stimulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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“…Receptors that belong to the "Gprotein coupled, seven transmembrane family of receptors (GPCRs)" are well represented on neutrophils, and the function of one of these, the formyl peptide receptor (FPR1) has been extensively studied. This receptor is a member of the chemoattractant receptor subfamily that recognizes N-formylated peptides [3][4][5]. As such peptides are derived from bacterial or mitochondrial proteins, it has been proposed that a primary FPR1 function is to promote trafficking of phagocytic myeloid cells to sites of infection and tissue damage, where they exert antibacterial effector functions and clear cell debris.…”

Section: Introductionmentioning

confidence: 99%

Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identified through screening of a compound library

Forsman

Kalderén

Nordin

et al. 2011

Biochemical Pharmacology

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The neutrophil formyl peptide receptors (FPR1 and FPR2) are G-protein coupled receptors that can induce pro-inflammatory as well as anti-inflammatory activities when activated. Accordingly, these receptors may become therapeutic targets for the development of novel drugs to be used for reducing the inflammation induced injuries in asthma, rheumatoid arthritis, Alzheimer's disease, cardiovascular diseases and traumatic shock. We screened a library of more then 50 K small compounds for an ability of the compounds to induce a transient rise in intracellular Ca 2+ in cells transfected to express FPR2 (earlier called FPRL1 or the lipoxin A 4 receptor). Ten agonists hits were selected for further analysis representing different chemical series and five new together with five earlier described molecules were further profiled.. Compounds 1 -10 gave rise to a calcium response in the FPR2 transfectants with EC 50 values ranging from 4 x 10 -9 M to 2 x 10 -7 M. All 10 compounds activated human neutrophils to release superoxide , and based on the potency of their activity, the three most potent activators of the neutrophil NADPH-oxidase were further characterized. These three agonists were largely resistant to inactivation by neutrophil produced reactive oxygen species and shown to trigger the same functional repertoire in neutrophils as earlier described peptide agonists. Accordingly they induced chemotaxis, granule mobilization and secretion of superoxide. Interestingly, the oxidase activity was largely inhibited by cyclosporine H, an FPR1 selective antagonist, but not by PBP10, an FPR2 selective inhibitor, suggesting that FPR1 is the preferred receptor in neutrophils for all three agonists.

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