The CC chemokine receptor 3 CCR3 is functionally expressed on eosinophils but not on neutrophils

Höchstetter, Renate; Dobos, Gustav; Kimmig, Daniela; Dulkys, Yasmin; Kapp, Alexander; Elsner, Jörn

doi:10.1002/1521-4141(200010)30:10<2759::aid-immu2759>3.0.co;2-a

Cited by 26 publications

(17 citation statements)

References 23 publications

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“…Given the recent discovery of CCR1 on neutrophils (21), we investigated whether neutrophils in whole blood expressed functional CCR3. Bonnechi et al (26) have previously demonstrated CCR3 mRNA expression in neutrophils following incubation with IFN-␥, although others have claimed that this was due to eosinophil contamination (27). We were able to demonstrate low level surface expression of CCR3 on neutrophils, which was lost upon purification.…”

Section: Discussionsupporting

confidence: 49%

Eotaxin (CCL11) and Eotaxin-2 (CCL24) Induce Recruitment of Eosinophils, Basophils, Neutrophils, and Macrophages As Well As Features of Early- and Late-Phase Allergic Reactions Following Cutaneous Injection in Human Atopic and Nonatopic Volunteers

Menzies‐Gow

Ying

Sabroe

et al. 2002

The Journal of Immunology

220

150

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Eotaxin and eotaxin-2, acting through CCR3, are potent eosinophil chemoattractants both in vitro and in animal models. In this study we examined the capacity of eotaxin and eotaxin-2 to recruit eosinophils and other inflammatory cells in vivo in human atopic and nonatopic skin. Skin biopsies taken after intradermal injection of eotaxin and eotaxin-2 were examined by immunohistochemistry. Allergen- and diluent-challenged sites were used as positive and negative controls. Eotaxin and eotaxin-2 produced a dose- and time-dependent local eosinophilia of comparable intensity in both atopic and nonatopic individuals. This was associated with an acute wheal and flare response at the site of injection and development of a cutaneous late phase reaction in a proportion of subjects. There was an accompanying decrease in mast cell numbers. Both chemokines also induced the accumulation of basophils and an unexpected early infiltration of neutrophils. Macrophages were prominent at the 24-h point. Although there was surface CCR3 expression on neutrophils in whole blood, we were unable to demonstrate any functional neutrophil responses to eotaxin in vitro. Thus, intradermal injection of eotaxin and eotaxin-2 in humans induced infiltration of eosinophils and other inflammatory cells as well as changes consistent with CC chemokine-induced mast cell degranulation.

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Section: Discussionsupporting

confidence: 49%

Eotaxin (CCL11) and Eotaxin-2 (CCL24) Induce Recruitment of Eosinophils, Basophils, Neutrophils, and Macrophages As Well As Features of Early- and Late-Phase Allergic Reactions Following Cutaneous Injection in Human Atopic and Nonatopic Volunteers

Menzies‐Gow

Ying

Sabroe

et al. 2002

The Journal of Immunology

220

150

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“…45 There is some controversy regarding the expression of CCR3 by neutrophils. Although there is a suggestion that CCR3 expression by neutrophils may be due to contamination by eosinophils, 46 other reports have clearly documented that neutrophils can express CCR3. 45,47 In our study, greater than 70% of purified neutrophils (defined as GR1-expressing granulocytes) from blm-treated mice expressed CCR3 (Figure 6), thus indicating that in certain circumstances neutrophils may express this receptor.…”

Section: Discussionmentioning

confidence: 99%

Role of Eotaxin-1 (CCL11) and CC Chemokine Receptor 3 (CCR3) in Bleomycin-Induced Lung Injury and Fibrosis

Huaux

Gharaee−Kermani

Liu

et al. 2005

The American Journal of Pathology

107

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Eotaxin-1/CCL11 and its receptor CCR3 are involved in recruitment of eosinophils to diverse tissues, but their role in eosinophil recruitment in pulmonary fibrosis is unclear. The present study examined the pulmonary expression of CCL11 and CCR3 during bleomycin (blm)-induced lung injury and determined their importance in the recruitment of inflammatory cells and the development of lung fibrosis. In mice, blm induced a marked pulmonary expression of CCL11 and CCR3. Immunostaining for CCR3 revealed that this receptor was not only expressed by eosinophils but also by neutrophils. CCL11-deficient (CCL11 ؊/؊ ) mice developed significantly reduced pulmonary fibrosis. Expression of profibrotic cytokines such as transforming growth factor-␤1 was diminished in the absence of CCL11. Furthermore, increased lung expression of CCL11 significantly enhanced blm-induced lung fibrosis and production of profibrotic cytokines. These effects were also associated with an increase of eosinophil and neutrophil pulmonary infiltration. In contrast, mice treated with neutralizing CCR3 antibodies developed significantly reduced pulmonary fibrosis, eosinophilia, neutrophilia, and expression of profibrotic cytokines. Together, these data suggest that CCL11 and CCR3 are important in the pulmonary recruitment of granulocytes and play significant pathogenic roles in blm-induced lung fibrosis.

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“…However, direct effects of eotaxin1 on these cell types cannot be ruled out. There is evidence for CCR3 on human neutrophils (Bonecchi et al, 1999;Menzies-Gow et al, 2002); however, this is controversial (Hochstetter et al, 2000), and no functional effect of eotaxin1 agonism has been established (Menzies-Gow et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

A Potent Human Anti-Eotaxin1 Antibody, CAT-213: Isolation by Phage Display and in Vitro and in Vivo Efficacy

Main

Handy

Wilton

et al. 2006

J Pharmacol Exp Ther

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The CC chemokine, eotaxin1 (CCL11) is an important regulator of eosinophil function. A marked accumulation of eosinophils in tissues has been correlated with the up-regulation of eotaxin1 expression in several diseases. The potential therapeutic value of neutralizing the effects of eotaxin1 in inflammatory conditions (including asthma) is under investigation. A human singlechain fragment variable antibody that neutralizes human eotaxin1 (CAT-212) was produced using antibody phage display and converted to whole antibody IgG4 format (CAT-213). A novel approach to lead optimization in which the length of the variable heavy chain complementarity-determining region 3 was reduced by one amino acid resulted in an increase in potency of Ͼ1000-fold compared with the parent anti-eotaxin1 antibody. The optimized antibody binds eotaxin1 with high affinity (80.4 pM) and specificity. CAT-213 and CAT-212 do not bind or neutralize a range of other human proteins including human monocyte chemoattractant protein-1, a structurally similar chemokine. CAT-213 neutralizes the ability of eotaxin1 to cause an increase in intracellular calcium signaling (with an IC 50 value of 2.86 nM), migration of CCR3-expressing L1.2 cells (with an IC 50 value of 0.48 nM), and inhibition of the eotaxin1-evoked shape change of human eosinophils in vitro (with an IC 50 of 0.71 nM). Local administration of CAT-213 to mice (1-100 g kg Ϫ1 ) attenuates dermal eosinophilia induced by human eotaxin1, achieving Ͼ90% inhibition of eosinophil influx. CAT-213 may therefore be of therapeutic value in inhibiting diseases in which eotaxin1 and eosinophils play a major role, for example, severe asthma.

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The CC chemokine receptor 3 CCR3 is functionally expressed on eosinophils but not on neutrophils

Cited by 26 publications

References 23 publications

Eotaxin (CCL11) and Eotaxin-2 (CCL24) Induce Recruitment of Eosinophils, Basophils, Neutrophils, and Macrophages As Well As Features of Early- and Late-Phase Allergic Reactions Following Cutaneous Injection in Human Atopic and Nonatopic Volunteers

Eotaxin (CCL11) and Eotaxin-2 (CCL24) Induce Recruitment of Eosinophils, Basophils, Neutrophils, and Macrophages As Well As Features of Early- and Late-Phase Allergic Reactions Following Cutaneous Injection in Human Atopic and Nonatopic Volunteers

Role of Eotaxin-1 (CCL11) and CC Chemokine Receptor 3 (CCR3) in Bleomycin-Induced Lung Injury and Fibrosis

A Potent Human Anti-Eotaxin1 Antibody, CAT-213: Isolation by Phage Display and in Vitro and in Vivo Efficacy

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