Cutting Edge: Expression of the C-C Chemokine Receptor CCR3 in Human Airway Epithelial Cells

Stellato, Cristiana; Brummet, Mary; Plitt, James R.; Shahabuddin, Syed; Baroody, Fuad M.; Liu, Mark C.; Ponath, Paul D.; Beck, Lisa A.

doi:10.4049/jimmunol.166.3.1457

Cited by 108 publications

(73 citation statements)

References 27 publications

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“…Our data showing that murine CCR3 is predominantly expressed by eosinophils are consistent with previous studies (19,20). These observations suggest that leukocyte recruitment in chronic allergic inflammation is orchestrated, at least in part, via CCR3 signaling in eosinophils, although we cannot exclude signal transduction events in other cells such as basophils and epithelial cells, because they have been shown to express low levels of CCR3 at least in the human system (21,22). Interestingly, only eosinophil trafficking is impaired in the eotaxin-1͞2-deficient mice, suggesting that other CCR3 ligands provide sufficient stimulation to induce the infiltration by other cell types.…”

Section: Discussionsupporting

confidence: 82%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

194

173

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To clarify the role and regulation of eosinophils, we subjected several key eosinophil-related genetically engineered mice to a chronic model of allergic airway inflammation aiming to identify results that were independent of the genetic targeting strategy. In particular, mice with defects in eosinophil development (⌬dbl-GATA) and eosinophil recruitment [mice deficient in CCR3 (CCR3 knockout) and mice deficient in both eotaxin-1 and eotaxin-2 (eotaxin-1͞2 double knockout)] were subjected to Aspergillus fumigatus-induced allergic airway inflammation. Allergen-induced eosinophil recruitment into the airway was abolished by 98%, 94%, and 99% in eotaxin-1͞2 double knockout, CCR3 knockout, and ⌬dbl-GATA mice, respectively. Importantly, allergen-induced type II T helper lymphocyte cytokine production was impaired in the lungs of eosinophil-and CCR3-deficient mice. The absence of eosinophils correlated with reduction in allergen-induced mucus production. Notably, by using global transcript expression profile analysis, a large subset (29%) of allergen-induced genes was eosinophil-and CCR3-dependent; pathways downstream from eosinophils were identified, including in situ activation of coagulation in the lung. In summary, we present multiple lines of independent evidence that eosinophils via CCR3 have a central role in chronic allergic airway disease.allergy ͉ asthma ͉ chemokine ͉ cytokine

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Section: Discussionsupporting

confidence: 82%

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Fulkerson

Fischetti

McBride

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

194

173

View full text Add to dashboard Cite

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“…Furthermore, cell surface binding of both eotaxin-3 and IP-10 to BEAS-2B cells was equally and completely sensitive to pronase pretreatment, suggesting that the non-GAG cell binding sites of eotaxin-3 may be mediated by the protein component or non-GAG sugar moieties of cell surface proteoglycans, or by entirely different cell surface proteins. It has been shown that BEAS-2B cells express low levels of CCR3 receptor on their surface [36]. However, we found that addition of an anti-CCR3 blocking mAb to BEAS-2B cells during IL-4 stimulation did not alter the eotaxin-3 surface binding (data not shown), which argues against a significant role of CCR3 in eotaxin-3 cell surface association in airway epithelial cells.…”

Section: Discussioncontrasting

confidence: 53%

Membrane‐bound eotaxin‐3 mediates eosinophil transepithelial migration in IL‐4‐stimulated epithelial cells

et al. 2006

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Epithelial cells play an important role in orchestrating mucosal immune responses. In allergic‐type inflammation, epithelial cells control the recruitment of eosinophils into the mucosa. Th2‐type cytokine‐driven release of eosinophil‐active chemokines from epithelial cells directs eosinophil migration into the mucosal epithelium. CCR3, the main eosinophil chemokine receptor, regulates this process; however, the respective contribution of individual CCR3 ligands in eosinophil transepithelial migration is less well understood. Using an in vitro transepithelial chemotaxis system, we found that eotaxin‐3 produced by IL‐4‐stimulated airway epithelial cells and CCR3 on eosinophils exclusively mediate eosinophil transepithelial migration. Eotaxin‐3 protein levels were also increased in the nasal mucosal epithelium recovered from allergic patients as compared to non‐allergic patients. Surprisingly, eotaxin‐3 in IL‐4‐stimulated airway epithelial cells was predominantly cell surface bound, and the cell surface form was critical for eosinophil transepithelial migration. Eotaxin‐3 cell surface association was partially glycosaminoglycan (GAG) dependent, but was completely protein dependent, suggesting that eotaxin‐3 associates with both GAG and cell surface proteins. We thus provide evidence that cell surface‐associated eotaxin‐3 is the critical IL‐4‐dependent chemotactic signal mediating eosinophil transepithelial migration in the setting of allergic inflammation.

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“…In contrast, surface expression of CCR3 or CX3CR1 was similar in iDCs and Hi-DCs. Lack of correlation between mRNAs and protein expression was observed in cytokine-stimulated human airway epithelial cells, and the possibility of translational regulation of CCR3 by hypoxia was suggested (49). The increase in CCR2 surface expression was a novel finding and raised the question of the functional response of Hi-DCs to the chemokine receptor -specific ligands.…”

Section: Hypoxia and Differentiation Of Dendritic Cells Mol Cancer Rementioning

confidence: 98%

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

Ricciardi

Elia

Cappello

et al. 2008

Molecular Cancer Research

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Hypoxia is a condition of low oxygen tension occurring in inflammatory tissues. Dendritic cells (DC) are professional antigen-presenting cells whose differentiation, migration, and activities are intrinsically linked to the microenvironment. DCs will home and migrate through pathologic tissues before reaching their final destination in the lymph node. We studied the differentiation of human monocytes into immature DCs (iDCs) in a hypoxic microenvironment. We generated iDC in vitro under normoxic (iDCs) or hypoxic (Hi-DCs) conditions and examined the hypoxia-responsive element in the promoter, gene expression, and biochemical KEGG pathways. Hi-DCs had an interesting phenotype represented by up-regulation of genes associated with cell movement/migration. In addition, the Hi-DC cytokine/receptor pathway showed a dichotomy between down-regulated chemokines and up-regulated chemokine receptor mRNA expression. We showed that CCR3, CX3CR1, and CCR2 are hypoxia-inducible genes and that CCL18, CCL23, CCL26, CCL24, and CCL14 are inhibited by hypoxia. A strong chemotactic response to CCR2 and CXCR4 agonists distinguished Hi-DCs from iDCs at a functional level. The hypoxic microenvironment promotes the differentiation of Hi-DCs, which differs from iDCs for gene expression profile and function. The most prominent characteristic of Hi-DCs is the expression of a mobility/migratory rather than inflammatory phenotype. We speculate that Hi-DCs have the tendency to leave the hypoxic tissue and follow the chemokine gradient toward normoxic areas where they can mature and contribute to the inflammatory process. (Mol Cancer Res 2008;6(2):175 -85)

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Cutting Edge: Expression of the C-C Chemokine Receptor CCR3 in Human Airway Epithelial Cells

Cited by 108 publications

References 27 publications

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation

Membrane‐bound eotaxin‐3 mediates eosinophil transepithelial migration in IL‐4‐stimulated epithelial cells

Transcriptome of Hypoxic Immature Dendritic Cells: Modulation of Chemokine/Receptor Expression

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