Neutrophils constitute the first line of host defense during infection and inflammation. By elimination of pathogens, they represent a major component of the innate immune response . They are produced in the bone marrow and after maturation, they are released into the circulation [2–4]. Homeostasis is regulated by a balance of neutrophil production, release from the bone marrow, and clearance from the circulation . Neutrophils are characterized by a circulating half-life of 6–8 h and are produced at a rate of 5 × 1010–10 × 1010 cells/day by the bone marrow . Less than 2% of the total body of mature neutrophils is circulating under basal conditions .
Recruitment of leukocytes into inflamed tissue in response to infection or stress is crucial for host defense . During the interaction with endothelial cells, neutrophils are exposed to chemokines and selectins, which induce integrin activation and neutrophil recruitment . Chemokines are a family of small secreted cytokines and play a crucial role in leukocyte activation and trafficking into inflamed tissue through interacting with G-protein coupled receptors (GPCRs), which are expressed on the surfaces of their target cells [9–11]. The activation of GPCRs leads to an activation of a signaling cascade, which ultimately leads to integrin activation [12▪▪]. Activated integrins can subsequently bind to their counter-receptors on endothelial cells and mediate slow rolling, adhesion, and transmigration [13,14].
Chemokines can be classified into four subfamilies – CXC, CC, C, or CX3C – based on their number and spacing of conserved cysteine residues near the N-terminus [11,15,16]. CXC, CC, and CX3C chemokines have four conserved cysteines, whereas C chemokines have only two. CXC and CX3C chemokines are differentiated by the presence of one (CXC) or three (CX3C) amino acids between the first and the second cysteine. However, the two cysteines of CC chemokines are adjacent. The nomenclature of chemokines is a combination of their subclass followed by ‘L’ for ligand and a specific number [15,17].
THE CXCL12/CXC CHEMOKINE RECEPTOR TYPE 4 AXIS
GPCRs consist of an α-subunit and a βγ-complex, which remain associated to the guanine nucleotide GDP at basal state. CXC chemokine receptor type 4 (CXCR4) is a GPCR belonging to the class I or rhodopsin-like GPCR family [18,19] and is specific for the chemokine CXCL12. CXCR4 is formed by 352 amino acid residues containing an N-terminal domain, seven transmembrane domains, three extracellular loops, three intracellular loops, and a C-terminal domain .
The CXCL12 cDNA clone was first isolated in 1993 by Tashiro et al. from a murine bone marrow stromal cell line . The gene was originally named stromal cell-derived factor-1 (SDF-1). CXCL12 is a homeostatic chemokine and mainly localized in bone marrow stromal cells. Until recently, the role of CXCL12/CXCR4 in inflammatory immune response remained unclear. However, recent studies demonstrated that CXCL12 and CXCR4 participate in tissue infiltration of neutrophils and lymphocytes after inflammatory stimuli [22,23]. Additionally, CXCL12 is a major regulator of hematopoietic cell homing to the bone marrow . Under normal conditions, CXCR4 is mainly expressed in the hematopoietic and immune systems.
CXC CHEMOKINE RECEPTOR TYPE 4-INDUCED SIGNALING
Binding of CXCL12 to CXCR4 induces Gαi-mediated signaling resulting in the activation of Ras/mitogen-activated protein (MAP) kinases, phosphatidylinositol 3-kinase (PI3K), and Akt. These signaling pathways participate in a variety of physiological responses such as chemotaxis, cell survival, proliferation, intracellular calcium flux, and gene transcription (Fig. 1).
Binding of a chemokine to its receptor may induce different cellular responses, including reorganization of the actin cytoskeleton, upregulation, of integrin expression, and integrin activation, adhesion, migration, and chemotaxis . In line with this, CXCL12/CXCR4-induced chemotaxis and neutrophil migration plays a crucial role in inflammatory diseases.
CXCR4-mediated chemotaxis is basically mediated by PI3K [26▪]. Signaling via the PI3K pathway triggers activation of Akt-dependent, PAK-dependent, and Cdc42-dependent pathways involved in cell polarization, actin polymerization, and neutrophil migration [27,28]. The other pathway that is triggered by CXCR4 engagement activates ERK (extracellular signal receptor kinase). ERK translocates to the nucleus and activates several transcription factors and leads to changes in gene expression and cell cycle progression.
ROLE OF CXC CHEMOKINE RECEPTOR TYPE 4 IN NEUTROPHIL HOMEOSTASIS
CXCR4 plays a dual role in neutrophil homeostasis. Under physiological conditions, upregulation of CXCR4 on circulating neutrophils supports homing to the bone marrow, where these cells undergo apoptosis and are phagocytosed by stromal macrophages [29,30]. The numbers of circulating neutrophils are strikingly stable in healthy humans [31,32] and mice . To exit the bone marrow, neutrophils have to migrate across the bone marrow endothelium and pass through cell–cell junctions and cell body of the endothelium [2,34,35]. CXCR4 levels on immature neutrophils are very high, whereas CXCR4 levels on mature neutrophils are low. Interaction of CXCR4 and CXCL12 results in retaining neutrophils within the bone marrow environment. Therefore, mature neutrophils, which express only low levels of CXCR4, can leave the bone marrow and enter the circulation. Different studies showed a cross-talk between CXCR4/CXCL12 and the VLA-4–VCAM-1 axis concerning the retention and release of neutrophils from the bone marrow under homeostatic conditions .
CXCR4-induced homing of neutrophils to the bone marrow stimulates G-CSF (colony stimulating factor) production, which constitutes the homeostatic link between clearance and production/release . G-CSF is a major mobilizing cytokine and a regulator of physical granulopoiesis by increasing the proliferation, differentiation, and survival of neutrophil precursors . Different studies indicated a decreased expression of CXCL12 in the bone marrow and CXCR4 expression on neutrophils by G-CSF treatment [38–40]. These findings suggest that disruption of CXCR4 signaling is the main factor mediating neutrophil release by G-CSF.
A defect in CXCR4 results in WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), which is an immunodeficiency disorder . Myelokathexis refers to the retention of mature neutrophils in the bone marrow, resulting in neutropenia. Most patients with WHIM syndrome are panleukopenic, which is the major cellular mechanism in this described disease . Affected patients show an increased number of neutrophils in the bone marrow, initiated by autosomal dominant inheritance of carboxyl terminal truncation mutations that remove 10–19 amino acids from CXCR4 . This mutation results in an enhanced sensitivity to CXCL12 and promotes abnormal neutrophil retention [44–46]. Deletion of CXCR4 in murine myeloid cells results in neutrophil release into the blood [1,47,48]. Patients with WHIM are treated with G-CSF and intravenous immunoglobulin. However, the treatment strategy has a number of disadvantages including nonspecificity and high cost .
In addition to its crucial roles in neutrophil homeostasis, CXCR4 is associated with the pathophysiology of different inflammatory diseases, including autoimmune diseases, ischemic injuries, and lung diseases. The diverse functions of CXCR4 in inflammation and the discovery of therapeutic strategies during recent years will be highlighted in this review.
CXC CHEMOKINE RECEPTOR TYPE 4 ANTAGONISTS
The three major categories of CXCR4 antagonists under clinical investigation include small peptide antagonists, nonpeptide antagonists, and antibodies. The pivotal role of CXCR4 antagonists in inflammatory diseases (Fig. 2) will be described in more detail in the following sections.
Peptide-based CXCR4 antagonists are derived from naturally occurring substances, including tachyplesin and polyphemusin . Synthetic analogues were subsequently synthesized and some of these, like T140, are unstable in serum. Due to this disadvantage, analogues of T140 were evolved, including TC14012, TN14003, and TZ14001. Preclinical studies demonstrated the ability of TN14003 to prevent metastasis, and improvement of posthematopoietic stem cell (HSC) transplant bone marrow recovery in murine experiments.
The CXCR4 antagonists plerixafor (Mozobil, formerly AMD3100) and AMD3465 belong to the group of nonpeptide antagonists. Both are reversible antagonists of CXCR4, plerixafor being a bicyclam and AMD3465 an N-pyridinylmethylene monocyclam derivate . AMD3100 was first described for its potent activity against HIV infection [52,53]. In an initial (phase I) clinical trial, administration of plerixafor showed leukocytosis and an increased CD34+ HSC count in peripheral blood [54,55]. In a phase II study, the combination of AMD3100 with G-CSF showed a stronger mobilization of CD34+ cells to the circulation than G-CSF alone . Phase III studies in myeloma and non-Hodgkin lymphoma (NHL) patients verified these findings [57,58]. On the basis of these findings, the CXCR4 antagonist plerixafor was approved for clinical use by the European Medicines Agency (EMA) in July 2003 and by the US Food and Drug Administration (FDA) in December 2008.
MDX-1338 (BMS-936564) is a human anti-CXCR4 monoclonal antibody that blocks the binding of CXCL12 to its receptor resulting in a decreased intracellular calcium surge and chemotaxis .
CXC CHEMOKINE RECEPTOR TYPE 4 ANTAGONISTS AND INFLAMMATORY DISEASES
The following sections summarize current knowledge about the CXCL12/CXCR4 axis in inflammatory diseases and discuss its potential as a pharmaceutical target.
Rheumatoid arthritis (RA) is an autoimmune disease, which affects numerous joints in the body. It is characterized by chronic inflammation of multiple joints, proliferation of the synovial cells, and irreversible destruction of the cartilage and bone of the affected joints [60–63]. Due to this reaction, massive infiltration of neutrophils and macrophages to the inflamed joints and the release of pro-inflammatory cytokines (e.g., interleukin-1β and tumor necrosis factor-α) aggravate the inflammation and immune response .
Recently, different studies support the involvement of the CXCL12/CXCR4 axis in memory T-cell migration into the inflamed RA synovium. Nanki et al. observed an increased expression level of CXCR4 in memory T cells and, apart from this, an exceedingly high concentration of CXCL12 in the synovium of RA patients. Furthermore, they could also show that CXCL12 stimulates the migration of the memory T cells and inhibits T-cell apoptosis, which clearly indicates the crucial role of the CXCL12/CXCR4 axis in T-cell accumulation in the RA synovium.
Blocking CXCL12 in a chemotaxis assay of T helper 1 cells toward RA synovial fluid suggests that the CXCL12/CXCR4 axis is important for T helper cell I migration in RA. Studies in which CXCR4 was eliminated or blocked showed a reduced severity of collagen-induced arthritis, without modulating the humoral immunity [66–68]. In addition, Tamamura et al. verified an anti RA-activity of a T140 analogue (4F-benoyl-TN14003) by assessing its effects on humoral and cellular immunity. This described CXCR4 antagonist inhibits CXCL12-mediated migration of memory T cells. In addition to these, several other CXCR4 antagonists including T140 and T22 are known to reduce the activity of RA [69,70].
Inflammatory bowel disease
An increasing number of studies have demonstrated that the development of the gut immune system is decisively influenced by the intestinal microbiota leading to the generation of immune homeostasis or the development of inflammatory bowel disease (IBD) . IBD, comprising Crohn's disease and ulcerative colitis, is a chronic inflammatory disease of the gastrointestinal tract with relapsing and remitting conditions. It is known that CD4+ T cells have crucial roles in the pathophysiology of IBD. The expression of chemokines and adhesion molecules on cells of the intestinal tissue regulate the recruitment of these immune cells. Therefore, regulation of the migration of leukocytes into the intestinal tissue illustrates a putative therapeutic option for patients with IBD.
The role of the CXCR4/CXCL12 axis in IBD has received very little attention. Nevertheless, Mikami et al. demonstrated a correlation between the activity of ulcerative colitis and the expression levels of CXCR4 on T cells. Further studies reported an expression of CXCR4 by intestinal epithelial cells and lamina propria cells, whereby CXCR4-positive cells in lamina propria are increased in IBD . The same group reported a stronger expression level of CXCL12 in intestinal tissues of ulcerative colitis patients than in those with Crohn's disease. Due to these findings, the CXCR4/CXCL12 axis seems specifically involved in the pathophysiology of ulcerative colitis.
Next, it is interesting to know whether blocking of the CXCL12/CXCR4 axis presents a new therapy option for patients with IBD. Administration of a CXCR4 inhibitor, TF14016, reduced colonic inflammation in a dextran sodium sulfate-induced colitis model . One explanation for the reduced inflammation could be that blocking of CXCR4 inhibits the production of pro-inflammatory cytokines .
Coronary artery and peripheral artery disease have a high incidence of morbidity and mortality . During the acute phase of ischemia, different factors, including hypoxia, oxidative stress, and inflammation, induce tissue damage [76,77]. In response to ischemia, neoangiogenesis and neovascularization are stimulated to restore organ function [78–81]. Regeneration is mediated by soluble factors, including CXCL12 and G-CSF, released by the ischemic tissues. This signaling results in CXCL12/CXCR4-dependent mobilization of progenitor cells (PGCs) from the bone marrow into the circulation and their migration into the injured tissue [82▪▪,83]. After injury, CXCL12 expression levels in the injured tissue increase inducing recruitment of CXCR4-expressing PGCs into the tissue [82▪▪,83].
Furthermore, inhibiting CXCR4 induces PGC mobilization from the bone marrow to the peripheral blood . Studies demonstrated that the blockade of CXCR4 leads to the mobilization of bone marrow progenitors from the bone marrow after ischemia/reperfusion injury and that this leads to an improved myocardial recovery [85▪▪,86▪▪].
Apart from the administration of AMD3100 for myocardial recovery, long-term treatment in mice alters fracture repair . Fracture repair is mediated by stem and PGC migration, homing, and differentiation. The reported results verified the impairment of fracture healing by inhibiting the recruitment and differentiation of osteo-chondrogenic, endothelial, and hematopoietic progenitors .
The presence of fibrocytes in blood and tissue is a characteristic of chronic lung diseases, including asthma, pulmonary hypertension, and pulmonary fibrosis . Fibrocytes are bone marrow-derived mesenchymal cell precursors, with monocyte morphology, expressing surface markers of leukocytes and HSCs, but also collagen I.
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease of the lungs. It is characterized by the proliferation of fibroblasts and deposition of extracellular matrix [89–91]. A number of studies demonstrated that the entering of bone marrow-derived circulating fibrocytes into injured tissues results in wound healing and fibrosis [92,93]. The CXCL12/CXCR4 axis represents the main pathway in regulation of fibrocyte migration in vitro and in vivo[94,95]. CXCR4-positive fibrocytes have been positively identified in the lung tissue of patients with IPF . Increased levels of CXCL12 in the lung and plasma of patients with IPF correlate with numbers of circulating fibrocytes, which was previously also found in animals [95,97]. The mobilization of circulatory fibrocytes and bone marrow-derived PGCs into injured lungs is controlled by the CXCL12/CXCR4 axis promoting the pathogenesis of pulmonary fibrosis [94,95].
Plerixafor prevents pulmonary fibrosis in bleomycin-induced pulmonary fibrosis in the murine system by inhibiting the recruitment of CD45+, CXCR4+, and collagen I+ fibrocytes into the injured lungs . In another study, the application of AMD3100 in bleomycin-induced lung injury only inhibited fibrocyte recruitment to the lung partially, suggesting that other chemokines may contribute to the migration of fibrocytes into the lung in vivo[99▪].
Recent studies have demonstrated the role of the CXCL12/CXCR4 axis in human diseases, including cancer, inflammation, and autoimmune diseases. As CXCR4 and its ligand CXCL12 have a pivotal role in different diseases, blocking this axis offers an attractive therapeutic option. However, further research is needed to investigate the effects of the blockade of CXCR4 in different inflammatory diseases. This is very important as the blockade of CXCR4 could also lead to a compromised elimination of invading pathogens. Currently, only plerixafor (AMD3100) is approved by the FDA for HSC mobilization. However, no approval exists for inflammatory diseases. Further studies and investigations are required to clarify the specific effect of CXCR4 antagonists in the wide range of inflammatory disease patterns.
The present work was supported by grants from the German Research Foundation (AZ 428/6-1 SFB and 1009/A5 to A.Z.).
Conflicts of interest
There are no conflicts of interest.
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This study demonstrated the pivotal role of AMD3100 as CXCR4 antagonist in ischemia/reperfusion injury. Administration of AMD3100 prolongs bone marrow progenitor mobilization and improves the recovery from injury, which illustrates the putative role of AMD3100 as a therapeutic agent in myocardial infarction.
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This study demonstrated the pivotal role of AMD3100 as CXCR4 antagonist in ischemia/reperfusion injury. Administration of AMD3100 prolongs bone marrow progenitor mobilization and improves the recovery from injury, which illustrates the putative role of AMD3100 as a therapeutic agent in myocardial infarction.
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99▪. Makino H, Aono Y, Azuma M, et al. Antifibrotic effects of CXCR4 antagonist in bleomycin-induced pulmonary fibrosis in mice. J Med Invest. 2013; 60:127–137.
Administration of AMD3100 directly inhibited the migration of human fibrocytes in response to CXCL12 in vitro, and reduced the trafficking of fibrocytes into the lungs treated with bleomycin in vivo. The results of this study suggest that the blockade of CXCR4 might be a useful strategy for therapy of patients with pulmonary fibrosis due to the inhibition of the migration of circulating fibrocytes.