Alternative titles; symbols
HGNC Approved Gene Symbol: CXCR2
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:218,125,294-218,137,251 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q35 | ?WHIM syndrome 2 | 619407 | Autosomal recessive | 3 |
Chemokines are a group of small, mostly basic molecules that regulate cell trafficking of various leukocytes through interactions with a subset of 7-transmembrane G protein-coupled receptors. Chemokines mainly act on neutrophils, monocytes, lymphocytes, and eosinophils and play a pivotal role in host defense mechanisms. CXCR2 is a promiscuous receptor for several CXCL chemokines, including CXCL1 (155730), CXCL2 (139110), CXCL3 (139111), CXCL5 (600324), CXCL6 (138965), CXCL7 (121010), and CXCL8 (IL8; 146930) (summary by Zlotnik and Yoshie, 2000).
Interleukin-8 (IL8, or CXCL8; 146930), growth-regulated gene (GRO1, or CXCL1; 155730), and neutrophil activating protein-2 (121010) are members of a large family of small secreted proteins (8-10 kD) with proinflammatory and reparative activities, including chemotaxis of neutrophils (Oppenheim et al., 1991). Two human cDNA clones that encode the receptors for these proteins were identified (Murphy and Tiffany, 1991). The 2 receptors, termed type 1 (146929) and type 2, have 77% amino acid identity. The type 1 IL8 receptor binds only IL8, while the type 2 IL8 receptor binds also GRO and NAP-2. The IL8 receptors are members of the rhodopsin superfamily of proteins whose dominant characteristic is 7 membrane-spanning domains.
Sprenger et al. (1994) showed that the IL8RB gene contains 3 exons, interrupted by 2 introns of 3 and 5.4 kb. The 1,065-bp open reading frame is encoded entirely in the third exon.
Ozcelik et al. (1991) identified this gene as a formyl peptide receptor-like gene and mapped it to chromosome 2 by Southern blot analysis of DNA from panels of somatic cell hybrids. See 136537. Mollereau et al. (1993) identified a pseudogene of the IL8RB gene.
Morris et al. (1992) used genomic clones for the 2 types of IL8 receptors in fluorescence in situ hybridization and in Southern analysis of somatic cell hybrid DNAs to demonstrate that both genes, as well as a pseudogene, map to chromosome 2q35. By interspecific backcross analysis, Cerretti et al. (1993) mapped the murine homolog of the IL8R2 gene to chromosome 1, near the Ity-Lsh-Bcg disease resistance locus.
Palter et al. (2001) characterized the IL8 system, which includes IL8, its receptors IL8RA (146929) and IL8RB, and its degradative enzyme aminopeptidase N (151530), in the human fallopian tube by immunohistochemistry. IL8 was found in the human fallopian tube predominantly in the epithelial cells and it was present in greater amounts in the distal compared with the proximal tube. IL8RA and IL8RB localized in the tube in similar patterns. Aminopeptidase N was found in tubal stromal tissue at the epithelial-stromal border and perivascularly. The authors concluded that the IL8 system may be an active component of tubal physiology and that aminopeptidase N may limit the systemic effects of epithelial IL8.
Tsai et al. (2002) demonstrated a role for rodent Cxcl1 and Cxcr2 in patterning the developing spinal cord. Signaling through Cxcr2, Cxcl1 inhibited oligodendrocyte precursor migration. The migrational arrest was rapid, reversible, and concentration dependent, and it reflected enhanced cell/substrate interactions. White matter expression of Cxcl1 was temporospatially regulated. Developing Cxcr2 null spinal cords contained reduced oligodendrocytes abnormally concentrated at the periphery. In mouse and rat slice preparations, Cxcl1 inhibited embryonic oligodendrocyte precursor migration, and widespread dispersal of postnatal precursors occurred in the absence of Cxcr2 signaling. The data suggested that a population of presumptive white matter by oligodendrocyte precursors is dependent on localized expression of CXCL1.
Weathington et al. (2006) reported that the collagen- or extracellular matrix (ECM)-derived PGP peptide shares sequence and structural homology with neutrophil chemokines, such as CXCL1 and CXCL2 (139110). In vivo studies in mice and in vitro studies using human cells showed that PGP was chemotactic for neutrophils. PGP chemotactic activity could be blocked by antibodies to CXCR1 (146929) and CXCR2 (IL8RB) in vivo and in vitro, and neutrophils failed to accumulate in Cxcr2 -/- mice after PGP challenge. Mass spectrometric analysis showed that mouse airways inflamed after exposure to lipopolysaccharide produced PGP peptides, resulting in neutrophil recruitment. Chronic exposure to PGP caused alveolar enlargement and right ventricular hypertrophy in mice. Weathington et al. (2006) found that individuals with chronic obstructive pulmonary disease (COPD; see 606963) had detectable PGP in bronchoalveolar lavage fluid. They concluded that PGP activity links ECM degradation with neutrophil recruitment in airway inflammation.
Alves-Filho et al. (2009) reported that Cxcr2 was dramatically downregulated in neutrophils of wildtype mice with severe sepsis, which correlated with reduced chemotaxis to Cxcl2 in vitro. Mice lacking Tlr2 (603028) did not downregulate Cxcr2 and exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival during severe sepsis. In vitro experiments showed that the Tlr2 agonist lipoteichoic acid (LTA) downregulated Cxcr2 expression and markedly inhibited neutrophil chemotaxis and actin polymerization induced by Cxcl2. Activation of wildtype neutrophils, but not Tlr2 -/- neutrophils, with LTA resulted in enhanced expression of Grk2 (ADRBK1; 109635). Activated neutrophils adoptively transferred to wildtype mice were less able to migrate to inflammatory sites. Alves-Filho et al. (2009) concluded that defective neutrophil migration during polymicrobial sepsis may be linked to a detrimental role of TLR2.
Using cryoelectron microscopy, Liu et al. (2020) determined the structure of human IL8-activated CXCR2 in complex with inhibitory G protein (Gi; see 139310). They also reported the crystal structure of CXCR2 bound to an allosteric antagonist. The results revealed a unique shallow mode of binding between CXCL8 and CXCR2 and also showed the interactions between CXCR2 and Gi. Further structural analysis of CXCR2 inactive and active states revealed a distinct activation process and competitive small-molecule antagonism of chemokine receptors.
WHIM Syndrome 2
In 2 sisters from Slovenia with WHIM syndrome-2 (WHIMS2; 619407), Auer et al. (2014) identified a homozygous frameshift mutation in the CXCR2 gene (146928.0001). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies in HeLa cells transfected with the mutation showed no detectable response to ligand stimulation, consistent with a loss of receptor function. The patients had neutropenia, myelokathexis, and recurrent infections. They did not have warts or hypogammaglobulinemia.
Associations Pending Confirmation
Eumycetoma is a tumorous fungal infection, typically of the hands or feet, characterized by the infiltration of large numbers of neutrophils. It is caused by Madurella mycetomatis, a pathogen that is abundant in the soil and on the vegetation of Sudan, where the disease is common. Van de Sande et al. (2007) noted that ELISA has shown near universal IgG seropositivity in mycetoma patients and controls from endemic areas, but no seropositivity in European controls, implying that most individuals in endemic areas are exposed to the pathogen, but only a small percentage develop disease. Van de Sande et al. (2007) studied 11 SNPs in genes involved in neutrophil function in 125 Sudanese mycetoma patients and 140 ethnically and geographically matched controls and found significant differences in allele distributions for SNPs in IL8, IL8RB, TSP4 (THBS4; 600715), NOS2 (163730), and CR1 (120620). Serum IL8 was significantly higher in patients compared with controls, while nitrite/nitrate levels were lower in patients and seemed to be associated with delayed wound healing. Van de Sande et al. (2007) concluded that there is a genetic predisposition toward susceptibility to mycetoma.
Cacalano et al. (1994) investigated the role of IL8R2 by cloning a murine gene with a high degree of homology to the 2 known human IL8R genes, IL8R2 and IL8R1 (146929). Using several different restriction enzymes and genomic DNA blots hybridized under low-stringency conditions, they found that the murine genome contains a single gene for the putative IL8 receptor (mIL-8Rh; Il8r2). When Cacalano et al. (1994) knocked out the Il8r2 gene by homologous recombination in embryonic stem cells, mice were generated that had lymphadenopathy, resulting from an increase in B cells, and splenomegaly, resulting from an increase in metamyelocytes, band, and mature neutrophils. Thus it is likely that this receptor participates in the expansion and development of neutrophils and B cells, possibly playing an inhibitory or negative role. The acute migration of neutrophils in response to injection of thioglycollate in the peritoneum was severely compromised (5 times slower) in these mice, suggesting that Il8r2 is the major mediator of neutrophil migration to sites of inflammation.
An unexpected finding by Cacalano et al. (1994) was a profound increase in the neutrophil and B cell populations. Cacalano et al. (1994) offered several possible explanations for these results, but strong evidence to support any one was lacking. Schuster et al. (1995) suggested that the neutrophil and B cell expansion was a compensatory change for poor resistance to normal flora and pathogen exposure and cited numerous references supporting their conclusion. They based this argument on studies in these mice and in patients with leukocyte adhesion deficiency (LAD; 116920) which is due to a defect in the CD18 gene (600065) and occurs not only in humans but also in dogs and cattle. Increased size of lymphoid organs and profound persistent neutrophilia with extensive granulopoietic activity outside of the bone marrow are hallmarks of this disease. Not down-regulating inflammatory cytokine production (for example, granulocyte-macrophage colony-stimulatory factor (138960)) in affected tissues could be expected to result in the observed histopathologic changes in the host, such as progressive neutrophilia. In support of this hypothesis, Schuster et al. (1995) noted that the neutrophilia is much lower in LAD animals raised under germ-free conditions than it is in animals raised conventionally.
In their response (which was published along with the comments of Schuster et al., 1995), the authors of Cacalano et al. (1994) noted that there are differences between the LAD-deficient animals and the Il8r2-minus mice: specifically, that while the Il8r2-minus mice do not show the extreme susceptibility to infections seen in LAD animals, increased neutrophil production still occurs (Moore et al., 1995). In order to test directly whether an impaired pathogenic response was involved in the increased neutrophil production, they compared Il8r2-minus mice bred in a specific pathogen-free (SPF) environment to those rederived in a germ-free (GF) condition. They offered initial results (Figure 1 in Schuster et al., 1995) suggesting that, in GF conditions, the blood level neutrophils are not elevated. This result showed that environmental pathogens are required for the neutrophilia observed in the Il8r2-minus mice. According to Moore et al. (1995), 'this may indicate that the inability to properly survey tissues and eliminate external pathogens results in the release of cytokines that, in turn, stimulate neutrophil production.'
Toxoplasma gondii is a major opportunistic pathogen during congenital infections and immunodeficiency and can be lethal if not appropriately treated. T. gondii is a potent inducer of type-1 cytokines, i.e., interleukin-2 (IL2; 147680) and gamma-interferon (IFNG; 147570), which are required for the host to survive infection. Overproduction of type-1 cytokines, however, can be fatal. Del Rio et al. (2001) found that mice with a targeted deletion of the homologous Cxcr2 gene did not express the protein on neutrophils and displayed defective neutrophil migration. The Cxcr2-deficient mice had lower tumor necrosis factor-alpha (TNFA; 191160) and Ifng production as well as higher numbers of parasites in the peritoneal cavity early after inoculation and greater brain cyst numbers during chronic infection. Additional experiments showed that mast cell-deficient mice also displayed defective neutrophil recruitment, suggesting that these cells serve as a major source for neutrophil-recruiting chemokines. Del Rio et al. (2001) concluded that CXCR2 and its ligands play an important protective role in resistance to T. gondii.
Keane et al. (2004) noted that glu-leu-arg (ELR+) CXC chemokines, such as CXCL1, CXCL2, CXCL3 (139111), CXCL5 (600324), CXCL6 (138965), and CXCL8, can mediate angiogenesis in the absence of preceding inflammation, and that CXCR2 is the receptor responsible for ELR+ CXC chemokine-mediated angiogenesis. They found that Lewis lung cancer tumors had significantly reduced growth in Cxcr2 -/- mice. In addition, there was less metastasis to the lung from heterotopic tumors in these mice. Keane et al. (2004) concluded that Cxcr2 mediates the angiogenic activity of ELR+ CXC chemokines in a preclinical model of nonsmall cell lung cancer.
Patients treated with high concentrations of inspired oxygen in the management of acute lung injury and acute respiratory distress syndrome may have an extended inflammatory response due to increased levels of reactive oxygen species. Sue et al. (2004) hypothesized that neutrophil recruitment to the lung during hyperoxia-induced lung injury is due in part to expression of CXCR2 ligands. Exposure of normal mice to 80% oxygen for 6 days caused 50% mortality and marked neutrophil sequestration in the lungs. Higher oxygen concentrations resulted in greater mortality. Using mice deficient in Cxcr2, Sue et al. (2004) showed that inhibition of Cxcl1 and Cxcl2/3 interaction with Cxcr2 significantly reduced neutrophil sequestration and lung injury and increased survival. They concluded that CXCL/CXCR2 association is critical during pathogenesis of hyperoxia-induced lung injury.
In 2 sisters from Slovenia with WHIM syndrome-2 (WHIMS2; 619407), Auer et al. (2014) identified a homozygous 1-bp deletion (c.968delA) in the CXCR2 gene, resulting in a frameshift and premature termination (His323fsTer6). The mutation, which was found by exome sequencing, segregated with the disorder in the family. In vitro functional expression studies in HeLa cells transfected with the mutation showed no detectable response to ligand stimulation, consistent with a loss of receptor function. The patients had neutropenia, myelokathexis, and recurrent infections. They did not have warts or hypogammaglobulinemia.
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Tsai, H.-H., Frost, E., To, V., Robinson, S., ffrench-Constant, C., Geertman, R., Ransohoff, R. M., Miller, R. H. The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration. Cell 110: 373-383, 2002. [PubMed: 12176324] [Full Text: https://doi.org/10.1016/s0092-8674(02)00838-3]
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