Alternative titles; symbols
HGNC Approved Gene Symbol: FPR1
Cytogenetic location: 19q13.41 Genomic coordinates (GRCh38): 19:51,745,172-51,751,878 (from NCBI)
The formyl peptide receptor is a G protein-coupled receptor of mammalian phagocytic cells that interacts with bacterial N-formyl peptides and activates microbicidal, secretory, and chemotactic functions of phagocytic cells in vitro. FPR is thought to mediate the response of phagocytic cells to invasion of the host by microorganisms (summary by Murphy et al., 1993).
Boulay et al. (1990) characterized 2 cDNA isolates for the N-formylpeptide receptor. The complex hybridization pattern obtained with restricted genomic DNA was consistent with either 2 genes encoding receptor isoforms or a single gene with at least 1 intron in the coding sequence. Sequence comparisons established that the N-formylpeptide receptor belongs to the G protein-coupled receptor superfamily.
Murphy et al. (1993) found that the FPR1 gene is organized into 3 exons and 2 introns that span 6 kb.
De Nardin et al. (1992) used a published cDNA sequence to identify a genomic fragment encoding FMLP receptor. They concluded that the gene is intronless.
Annexin A1 (ANXA1; 151690) has been shown to mediate antiinflammatory activities of glucocorticoids. Walther et al. (2000) showed that ANXA1 acts through the FPR on human neutrophils. Peptides derived from the unique N-terminal domain of ANXA1 serve as FPR ligands and trigger different signaling pathways in a dose-dependent manner. Lower peptide concentrations possibly found in inflammatory situations elicit Ca(2+) transients without fully activating the mitogen-activated protein kinase pathway. This causes a specific inhibition of the transendothelial migration of neutrophils and a desensitization of neutrophils toward a chemoattractant challenge. These findings identified ANXA1 peptides as novel, endogenous FPR ligands and established a mechanistic basis of ANXA1-mediated antiinflammatory effects.
Zhang et al. (2010) showed that showed that injury releases mitochondrial damage-associated molecular patterns (DAMPs) into the circulation with functionally important immune consequences. Mitochondrial DAMPs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through FPR1 and Toll-like receptor 9 (TLR9; 605474), respectively. Mitochondrial DAMPs promote PMN calcium ion flux and phosphorylation of mitogen-activated protein kinases (MAPKs), thus leading to PMN migration and degranulation in vitro and in vivo. Circulating mitochondrial DAMPs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial pathogen-associated molecular patterns (PAMPs) into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. Zhang et al. (2010) concluded that the release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation, and the systemic inflammatory response syndrome (SIRS).
Vacchelli et al. (2015) identified a loss-of-function allele (glu346 to ala, rs867228) of the FPR1 gene that was associated with poor metastasis-free and overall survival in breast and colorectal cancer patients receiving adjuvant chemotherapy. The therapeutic effects of anthracyclines were abrogated in tumor-bearing Fpr1 -/- mice due to impaired antitumor immunity. Fpr1-deficient dendritic cells failed to approach dying cancer cells and, as a result, could not elicit antitumor T cell immunity. Experiments performed in a microfluidic device confirmed that FPR1 and its ligand, annexin-1, promoted stable interactions between dying cancer cells and human or murine leukocytes. Vacchelli et al. (2015) concluded that their results highlighted the importance of FPR1 in chemotherapy-induced anticancer immune responses.
Osei-Owusu et al. (2019) demonstrated that LcrV, the needle cap protein of the Yersinia pestis type III secretion system (T3SS) that targets host immune cells for destruction, binds to the N-formylpeptide receptor (FPR1) on human immune cells to promote the translocation of bacterial effectors. FPR1-null U937 cells were resistant to Y. pestis T3SS-mediated killing. Cell migration assays showed that immune cell chemotaxis towards Y. pestis is mediated by the T3SS and FPR1. Osei-Owusu et al. (2019) found that the Y. pestis T3SS releases N-formylpeptides to activate FPR1 signaling. Fpr1-deficient mice had increased survival and antibody responses that are protective against plague. The authors identified a candidate resistance allele in humans (see 136537.0001) that protects neutrophils from destruction by the Y. pestis T3SS. Osei-Owusu et al. (2019) concluded that FPR1 is a plague receptor on immune cells in both humans and mice, and its absence or mutation provides protection against Y. pestis. Furthermore, plague selection of FPR1 alleles appears to have shaped human immune responses towards other infectious diseases and malignant neoplasms.
Ozcelik et al. (1991) mapped the FPR1 gene to human chromosome 19 by Southern analysis of rodent/human somatic cell hybrids and use of a cDNA probe. An FPR-like gene was also identified on chromosome 19 (136538) (Ozcelik et al., 1991). An FPR-like gene that mapped to chromosome 2 was found in fact to represent an interleukin 8 receptor (146928).
Bao et al. (1992) mapped the gene encoding the receptor for the chemotactic ligand FMLP to chromosome 19 using a panel of somatic cell hybrids. They identified 2 structural homologs of FPR that similarly mapped to chromosome 19. The structural homologs did not recognize the ligand FMLP, but were thought to represent chemotactic receptors. Bao et al. (1992) referred to them as orphan receptors and symbolized the genes FPRH1 and FPRH2.
Osei-Owusu et al. (2019) noted that phylogenetic analysis had shown that early duplication of FPR1 generated FPR2 in the chemotaxis locus of mammals. This was followed by a late duplication of FPR2 to yield FPR3 near the evolutionary origin of primates. FPR1 is the high-affinity receptor for N-formylpeptides, whereas FPR2 functions not only as a low-affinity receptor for these compounds but also recognizes other types of chemoattractants. Rodents generally have Fpr1 and an expanded family of Fpr2-derived receptors that are expressed in vomeronasal neurons and respond to olfactory stimuli. By contrast, Canidae (such as wolves, dogs, coyotes, and foxes) have lost Fpr1 and the ability to respond to N-formylpeptides, instead containing duplicated Fpr2 in their chemotaxis locus. Y. pestis causes plague in rabbits and a wide range of rodent species (rats, mice, prairie dogs, guinea pigs, and gerbils), whereas Canidae are resistant to plague disease. Although coyotes are frequently infected with Y. pestis through the consumption of plague-infected prey, these animals generate plague-protective F1 antibodies without developing disease symptoms. Osei-Owusu et al. (2019) hypothesized that plague resistance in Canidae may be related to the loss of FPR1 in these species.
Oldekamp et al. (2014) observed increased bacterial burden, neutrophil infiltration, and mortality in mice lacking Fpr1 or Fpr2 compared with wildtype mice following infection with Streptococcus pneumoniae in the subarachnoid space, a model of pneumococcal meningitis. Immunohistochemical analysis demonstrated increased glial cell density during meningitis in mice lacking Fpr1 or Fpr2. Oldekamp et al. (2014) concluded that FPR1 and FPR2 play an important role in the innate immune response against S. pneumonia in the central nervous system.
Osei-Owusu et al. (2019) found that, when infected with Yersinia pestis, bone marrow-derived macrophages (BMDMs) from Fpr1-null mice were partially resistant to Y. pestis type III secretion system (T3SS)-mediated killing, whereas BMDMs from wildtype mice were rapidly killed. Fpr1-null mice showed a delayed time to death by 2.25 days compared to wildtype mice when inoculated with Y. pestis, and had a small but significant increase in survival. In mouse models of pneumonic and bubonic plague, Y. pestis triggers neutrophil influx to the site of infection. Osei-Owusu et al. (2019) detected similar numbers of immune cells in inguinal tissues of Fpr1-null and wildtype mice 4 hours after intradermal inoculation with Y. pestis, indicating that during bubonic plague infection the Fpr1-null mutation predominantly blocks the injection of bacterial effectors without abolishing the neutrophil influx into infected tissues. All mice that died of plague displayed high bacterial load in spleens, but Y. pestis bacteria were not recovered from tissues of surviving Fpr1-null mice. Spleens of Fpr1-null survivors displayed a histology that was similar to that of naive mice, compared to those of wildtype and Fpr1-null mice that succumbed to plague, which showed destruction of white pulp and its replacement by fibrinoid necrosis lesions, representing massive depletion of spleen immune cells. Fpr1-null survivors developed high-titer antibodies against Caf1 antigen, which provide protective immunity against plague.
Yersinia Pestis Resistance
Osei-Owusu et al. (2019) identified FPR1 R190W as a candidate resistance allele in humans that protects neutrophils from destruction by the Yersinia pestis type III secretion system (T3SS), which targets immune cells for destruction. In a human donor whose neutrophils exhibited decreased T3SS translocation and reduced chemotaxis toward N-formylpeptide and Y. pestis, Osei-Owusu et al. (2019) identified a SNP in the FPR1 gene, rs5030880A-T, that designated an arg190-to-trp (R190W) substitution in extracellular loop 2 between transmembrane domains 4 and 5. The authors stated that this variant occurs in 11 to 13% of Europeans and Americans of European descent, 6 to 9% of Africans and Americans of African descent, and 20% of Asians. This donor did not carry the CCR5-delta-32 allele (601373.0001). Osei-Owusu et al. (2019) generated macrophages expressing FPR1 R190W and found that they exhibited reduced effector translocation during Y. pestis infection, and chemotoaxis experiments revealed reduced migration of R190W-expressing monocytes towards N-formylpeptide and Y. pestis compared to controls.
Bao, L., Gerard, N. P., Eddy, R. L., Jr., Shows, T. B., Gerard, C. Mapping of genes for the human C5a receptor (C5AR), human FMLP receptor (FPR), and two FMLP receptor homologue orphan receptors (FPRH1, FPRH2) to chromosome 19. Genomics 13: 437-440, 1992. [PubMed: 1612600] [Full Text: https://doi.org/10.1016/0888-7543(92)90265-t]
Boulay, F., Tardif, M., Brouchon, L., Vignais, P. The human N-formylpeptide receptor: characterization of two cDNA isolates and evidence for a new subfamily of G-protein-coupled receptors. Biochemistry 29: 11123-11133, 1990. [PubMed: 2176894] [Full Text: https://doi.org/10.1021/bi00502a016]
De Nardin, E., Radel, S. J., Lewis, N., Genco, R. J., Hammarskjold, M. Identification of a gene encoding for the human formyl peptide receptor. Biochem. Int. 26: 381-387, 1992. [PubMed: 1627151]
Murphy, P. M., Tiffany, H. L., McDermott, D., Ahuja, S. K. Sequence and organization of the human N-formyl peptide receptor-encoding gene. Gene 133: 285-290, 1993. [PubMed: 8224916] [Full Text: https://doi.org/10.1016/0378-1119(93)90653-k]
Oldekamp, S., Pscheidl, S., Kress, E., Soehnlein, O., Jansen, S., Pufe, T., Wang, J. M., Tauber, S. C., Brandenburg, L.-O. Lack of formyl peptide receptor 1 and 2 leads to more severe inflammation and higher mortality in mice with of (sic) pneumococcal meningitis. Immunology 143: 447-461, 2014. [PubMed: 24863484] [Full Text: https://doi.org/10.1111/imm.12324]
Osei-Owusu, P., Charlton, T. M., Kim, H. K., Missiakas, D., Schneewind, O. FPR1 is the plague receptor on host immune cells. Nature 574: 57-62, 2019. [PubMed: 31534221] [Full Text: https://doi.org/10.1038/s41586-019-1570-z]
Ozcelik, T., Murphy, P. M., Francke, U. Chromosomal assignment of genes for a formyl peptide receptor (FPR1), a structural homologue of the formyl peptide receptor (FPRL1) and a low affinity interleukin 8 receptor (IL8RA) in human. (Abstract) Cytogenet. Cell Genet. 58: 2023-2024, 1991.
Vacchelli, E., Ma, Y., Baracco, E. E., Sistigu, A., Enot, D. P., Pietrocola, F., Yang, H., Adjemian, S., Chaba, K., Semeraro, M., Signore, M., De Ninno, A., and 30 others. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350: 972-978, 2015. [PubMed: 26516201] [Full Text: https://doi.org/10.1126/science.aad0779]
Walther, A., Riehemann, K., Gerke, V. A novel ligand of the formyl peptide receptor: annexin I regulates neutrophil extravasation by interacting with the FPR. Molec. Cell 5: 831-840, 2000. [PubMed: 10882119] [Full Text: https://doi.org/10.1016/s1097-2765(00)80323-8]
Zhang, Q., Raoof, M., Chen, Y., Sumi, Y. Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C. J.: Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464: 104-107, 2010. [PubMed: 20203610] [Full Text: https://doi.org/10.1038/nature08780]