Critical Involvement of the Chemotactic Axis CXCR4/Stromal Cell-Derived Factor-1α in the Inflammatory Component of Allergic Airway Disease

Gonzalo, José-Ángel; Lloyd, Clare M.; Peled, Amnon; Delaney, Tracy; Coyle, Anthony J.; Gutierrez-Ramos, José-Carlos

doi:10.4049/jimmunol.165.1.499

Cited by 179 publications

(157 citation statements)

References 40 publications

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“…20,41 In agreement with our data is a recent study that indicates that SDF-1 and CxCR4 are directly involved in the asthmatic response in an ovalbumin model of asthma. 21 Thus, the role of CxCR4 during an allergic/asthmatic pulmonary response may reflect the altered immune environment leading to increased lung damage and airway reactivity. The present experiments add further information to the possible mechanism of how CxCR4 is involved.…”

Section: Discussionmentioning

confidence: 99%

“…19,20 Of these Th2 cell-expressed chemokine receptors, only CxCR4, and its ligand SDF-1, have been shown to be relevant during Th2-type allergic airway responses. 21 CxCR4, like many chemokine receptors, is a Gi-coupled receptor that is specific for SDF-1. 22,23 SDF has previously been shown to be chemotactic for a number of leukocyte populations, including neutrophils, monocytes, lymphocytes, and more recently, eosinophils.…”

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confidence: 99%

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AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

Lukacs

Berlin

Schols

et al. 2002

The American Journal of Pathology

195

149

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The role of specific chemokine receptors during allergic asthmatic responses has been relatively undefined. A number of receptors are preferentially expressed on Th2 cells, including CCR4, CCR8, and CxCR4. In the present study, we have examined the role of CxCR4 in the development of cockroach allergen-induced inflammation and airway hyperreactivity in a mouse model of asthma. Using a specific inhibitor of CxCR4, AMD3100, our results indicate that blocking this receptor has a significant effect in down-regulating the inflammation and pathophysiology of the allergen-induced response. Treatment of allergic mice with AMD3100 significantly reduced airway hyperreactivity, peribronchial eosinophilia, and the overall inflammatory responses. In addition, there was a shift in the cytokine profile that was observed in the AMD3100-treated animals. Specifically, there was a significant reduction in interleukin-4 and interleukin-5 levels and a significant increase in interleukin-12 and interferon-␥ levels within the lungs of treated allergic mice. Furthermore, there was a significant alteration in the local chemokine production of CCL22 (MDC) and CCL17 (TARC), two chemokines previously shown to be important in Th2-type allergen responses. Overall, specifically blocking CxCR4 using AMD3100 reduced a number of pathological parameters related to asthmatic-type inflammation.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

Lukacs

Berlin

Schols

et al. 2002

The American Journal of Pathology

195

149

View full text Add to dashboard Cite

show abstract

“…To determine whether the enhanced survival of SDF-1/CXCL12 transgene-expressing myeloid progenitor cells was being mediated through CXCR4, the receptor for SDF-1, bone marrow cells from the transgenic mice were pretreated for 30 min before plating and then the cells were plated with final concentrations of either 1 M, 0.1 M, or 0.01 M AMD-3100, a specific antagonist of SDF-1 binding to CXCR4 (29) that we previously demonstrated blocks SDF-1/CXCL12-induced activation of mitogen-activated protein kinase activity in the human factor-dependent cell line MO7e (10), or 10, 1, or 0.1 g/ml of anti-mouse CXCR4 Abs (23). As shown in Fig.…”

Section: Figurementioning

confidence: 99%

Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo

Broxmeyer

Cooper

Kohli

et al. 2003

The Journal of Immunology

153

143

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Hemopoiesis is regulated in part by survival/apoptosis of hemopoietic stem/progenitor cells. Exogenously added stromal cell-derived factor-1 ((SDF-1)/CXC chemokine ligand (CXCL)12) enhances survival/antiapoptosis of myeloid progenitor cells in vitro. To further evaluate SDF-1/CXCL12 effects on progenitor cell survival, transgenic mice endogenously expressing SDF-1/CXCL12 under a Rous sarcoma virus promoter were produced. Myeloid progenitors (CFU-granulocyte-macrophage, burst-forming unit-erythroid, CFU-granulocyte-erythrocyte-megakaryocyte-monocyte) from transgenic mice were studied for in vitro survival in the context of delayed addition of growth factors. SDF-1-expressing transgenic myeloid progenitors were enhanced in survival and antiapoptosis compared with their wild-type littermate counterparts. Survival-enhancing effects were due to release of low levels of SDF-1/CXCL12 and mediated through CXCR4 and Gαi proteins as determined by ELISA, an antagonist to CXCR4, Abs to CXCR4 and SDF-1, and pertussis toxin. Transgenic effects of low SDF-1/CXCR4 may be due to synergy of SDF-1/CXCL12 with other cytokines; low SDF-1/CXCL12 synergizes with low concentrations of other cytokines to enhance survival of normal mouse myeloid progenitors. Consistent with in vitro results, progenitors from SDF-1/CXCL12 transgenic mice displayed enhanced marrow and splenic myelopoiesis: greatly increased progenitor cell cycling and significant increases in progenitor cell numbers. These results substantiate survival effects of SDF-1/CXCL12, now extended to progenitors engineered to endogenously produce low levels of this cytokine, and demonstrate activity in vivo for SDF-1/CXCL12 in addition to cell trafficking.

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“…Cells incubated on ice with any of the chemokines showed no significant reduction of surface gpCCR4 expression after 60 min, showing that the washing steps incorporated in the protocol avoided any competition between the ligand and detecting mAb that would give a false impression of receptor internalization. The murine L1.2 cells constitutively express CXCR4 (40); therefore, human SDF-1␣, which also signals via murine CXCR4 (41), was included in the assay to determine whether CXCR4 down-regulation would affect surface CCR4 expression levels (heterologous desensitization). Stimulation of gpCCR4-transfected cells with human SDF-1␣ had no effect on surface CCR4 expression levels (Fig.…”

Section: Fig 5 Specific Chemotactic Responses Toward the Murine Andmentioning

confidence: 99%

The Identification, Characterization, and Distribution of Guinea Pig CCR4 and Epitope Mapping of a Blocking Antibody

Jopling¹,

Sabroe²,

Andrew³

et al. 2002

Journal of Biological Chemistry

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Th2 lymphocytes play a central role in the control and maintenance of allergic inflammation. The chemokine receptor CCR4 is preferentially expressed on the surface of Th2 lymphocytes polarised in vitro. However, CCR4 is found on the surface of a significant proportion of circulating memory T lymphocytes, some of which are capable of producing the Th1-associated cytokine interferon ␥. To investigate the function of CCR4 on guinea pig (gp) T lymphocytes, we identified the open-reading frame of gpCCR4, which encodes a 361-amino acid protein with 88 and 81% amino acid identity to human and murine CCR4 sequences, respectively. Cells transfected with gpCCR4 migrated toward the human and murine orthologues of the CCR4 ligands, macrophage-derived chemokine and thymus and activation-regulated chemokine. Surface expression of CCR4, using an anti-human CCR4 monoclonal antibody, 10E4, was detected on ϳ12% of guinea pig peripheral blood T helper cells, and CCR4 ؉ guinea pig thymocytes were detected in low numbers. However, CCR4؉ T helper cells constituted ϳ9% of the T lymphocyte population within the normal guinea pig lung and 52% of the guinea pig bronchoalveolar lavage fluid, which is consistent with a role for CCR4 in T lymphocyte development and trafficking through normal tissues. Subsequent analysis of chimeric chemokine receptors indicated that 10E4, a functional inhibitor of gpCCR4 responses, recognized the amino terminus of CCR4.Allergic inflammation of the lung in diseases such as asthma is largely controlled and maintained by the recruitment of antigen-specific T lymphocytes to the lung tissue (1). The Th2-type lymphocytes that predominate at sites of allergic inflammation secrete cytokines such as IL-4, IL-5 and IL-13, 1 which influence the actions of other leukocyte populations involved in the inflammatory response (2, 3). For example, IL-4 and IL-13 can induce B lymphocyte production of IgE (4, 5) and airway epithelial cell generation of eotaxin, which is central to eosinophil recruitment (6, 7), whereas IL-5 is a potent eosinophil maturation and survival factor (8, 9). Overexpression of IL-13 in the lung causes many of the histopathological and physiological features of asthma (10). Increasing evidence suggests that chemokines are important regulators of the selective trafficking of leukocytes in homeostasis, hematopoiesis, and inflammation (11). Chemokines can be divided into four subfamilies dependent upon the position of their amino-terminal cysteine residues; the two main chemokine groups are the CXCL and the CCL subfamilies (12), which signal via CXCR and CCR receptors belonging to the G-protein coupled receptor superfamily (13,14). The differential expression of chemokine receptors on the surface of leukocytes contributes to the selective recruitment of cells to specific sites, and, consequently, these receptors may provide useful targets for therapeutic intervention in the modulation of inflammatory disorders. Studies of T lymphocytes polarized in vitro have shown that Th1 cells preferentially express CC...

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Critical Involvement of the Chemotactic Axis CXCR4/Stromal Cell-Derived Factor-1α in the Inflammatory Component of Allergic Airway Disease

Cited by 179 publications

References 40 publications

AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity

Transgenic Expression of Stromal Cell-Derived Factor-1/CXC Chemokine Ligand 12 Enhances Myeloid Progenitor Cell Survival/Antiapoptosis In Vitro in Response to Growth Factor Withdrawal and Enhances Myelopoiesis In Vivo

The Identification, Characterization, and Distribution of Guinea Pig CCR4 and Epitope Mapping of a Blocking Antibody

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