Chemokines in allergic airway disease

doi:10.1016/S1471-4892(03)00069-9

Current Opinion in Pharmacology

Volume 3, Issue 4, August 2003, Pages 443-448

https://doi.org/10.1016/S1471-4892(03)00069-9 Get rights and content

Abstract

Expression of chemokine receptors on T helper 2 cells and eosinophils has been postulated to be the mechanism by which these cells are selectively recruited to the lung during allergic inflammatory reactions. Mouse models have provided evidence to show that blocking the ligands for these receptors is successful in abrogating the pathophysiological effects of allergen challenge. However, recent studies describing the effect of genetic deletions of these chemokine receptors have not confirmed the results obtained with ligand knockouts or neutralising antibodies. Coupled with the realisation that, because of a lack of species cross-reactivity, it is not possible to test small molecule antagonists against human receptors in the original in vivo animal models, the future of chemokine receptor therapeutics is in question. However, recent advances have been made regarding the therapeutic potential of blocking the chemokine receptors CCR3, CCR4 and CCR8 in allergic airway disease.

Introduction

Allergic inflammation, such as asthma, is a T helper (Th)2-driven response associated with the selective recruitment of allergen-specific Th2 cells to sites of inflammation. These Th2 cells influence the inflammatory response through generation of specific cytokines, including interleukin (IL)-4, IL-13 and IL-5. One important consequence of Th2 cell involvement is the associated influx of large numbers of eosinophils, which are thought to contribute to the pathogenesis of the disease. Allergic inflammation in the lung is characterised by airway hyperresponsiveness (AHR). Eosinophils, Th2 cells and mast cells can all contribute to AHR, although controversy remains over which cell type is the predominant effector of this response. In developing therapies for asthma, the goal is to inhibit AHR and not just leukocyte recruitment.

Chemokines are a group of structurally related chemotactic cytokines that signal through 7-transmembrane G-protein-coupled receptors expressed by leukocytes. The discovery that certain chemokine receptors are differentially expressed on the surface of effector T cells has suggested that this might be the mechanism by which Th2 cells are selectively recruited to the lung. In vitro analysis has determined that not only do effector T cells express a restricted repertoire of receptors but also that they preferentially migrate to the chemokines that bind these receptors 1., 2.. Thus, it has been shown that CCL11 (eotaxin), CCL22 (monocyte-derived chemokine), CCL17 (thymus and activation-regulated chemokine) and CCL1 (I-309 [human] or TCA-3 [mouse]) are chemokines which induce the selective migration of Th2 cells but not Th1 cells. CCL11 binds exclusively to the chemokine receptor (CCR)3, whereas CCL22 and CCL17 both interact with CCR4. CCL1 is the only known ligand for CCR8. Interestingly, CCR3 is also expressed by eosinophils, for which CCL11 is a potent chemoattractant. The only other chemokine receptor expressed by eosinophils is CCR1, but this is generally expressed at very low levels. Interest in CCR3, CCR4 and CCR8 as potential therapeutic targets in asthma developed when it was discovered that these receptors exhibited restricted expression profiles on cells believed to be involved in the asthmatic response. CCR3 is reported to be expressed by eosinophils, Th2 cells, mast cells and basophils, whereas CCR4 and CCR8 are expressed by Th2 cells (Figure 1). Thus, these chemokine receptors are potential targets for the treatment of allergic inflammation, as they have the advantage of being expressed by selective leukocyte populations.

In this review, we describe recent findings from in vivo studies of allergic inflammation regarding the function of chemokines and their receptors. These studies include those using both ligand blockade and receptor knockout (KO) strategies. We discuss how recent advances in the fields of chemokine biology and allergic airway inflammation allow us to better interpret some of the conflicting results. Finally we consider how the results of all of these studies impact on the search to find chemokine receptor antagonists for anti-asthma therapeutics.

Section snippets

CCL11 and CCR3

Multiple studies have shown that neutralisation of CCL11 results in a decrease in both airway inflammation and AHR 3., 4., 5.. More specifically, it has been shown that CCL11 blockade reduces trafficking of Th2 cells and eosinophils [6]. In contrast, the CCL11 KO mouse showed only partial protection against development of allergic airway inflammation, reinforcing the idea that there is a certain amount of redundancy in the chemokine network 7., 8.. Three members of the CCL11 family have been

CCL22, CCL17 and CCR4

Neutralising either CCL22 or CCL17 has been shown to abrogate lung eosinophilia and AHR 20., 21.. It was proposed that this was caused by inhibition of Th2 cell trafficking. Further studies utilised a model based on the adoptive transfer of allergen-specific effector T cells to track Th2 cell migration to the lung following allergen challenge in mice receiving anti-CCL22 antibodies [6]. These experiments established that CCL22 and CCR4 contribute to the recruitment of Th2 cells to the lung,

CCL1 and CCR8

The in vivo role of the CCL1/CCR8 chemokine axis in Th2-mediated inflammation is more controversial. Recent studies have shown that, although both CCL1 protein and CCR8 mRNA are upregulated in the murine lung following allergen sensitisation and challenge, neutralisation of the ligand has no effect on recruitment of Th2 cells to the lungs 24.••, 25.••. Interestingly, one of these studies reported no effect of CCL1 blockade on eosinophil recruitment [25^••], whereas the other reported a modest

CXCL12 and CXCR4

CXCR4 is expressed constitutively on all T cells and on a wide range of other cells, including CD34⁺ stem cells, B cells and monocytes. It is not, however, expressed by eosinophils. As deficiency of either CXCR4 or CXCL12 (SDF-1α) is lethal, it was originally hypothesised that CXCR4 played an important role in the homeostatic homing mechanism of multiple leukocyte populations. Therefore, it was surprising that blockade of this chemokine receptor with a blocking monoclonal antibody caused a

Chemokine receptor expression after allergen challenge of atopic asthmatics

To establish a role for specific chemokines and their receptors in allergic airway inflammation in humans, several studies have examined chemokine receptor expression on T cells within the lungs of asthmatic patients following allergen challenge. In one such study, significantly greater numbers of CCR4⁺ T cells were found in bronchial biopsies after segmental allergen challenge than in pre-challenge biopsies, biopsies from non-atopic patients or biopsies from patients with ‘Th1-type’ lung

Chemokine receptor expression is dynamic in vivo

There are various aspects of chemokine receptor biology that influence the conclusions drawn from individual studies in vitro and in vivo. The reported selectivity of chemokine receptor expression is appealing in terms of anti-inflammatory therapy, as it is possible to target selected leukocyte populations. However, our current knowledge of chemokine receptor expression has been gained largely from studies of isolated blood leukocytes and, in the case of T cells, on artificially polarised T

Relevance of mouse models to human disease

A comparison of the methodologies used in the animal studies cited in this review reveals some important differences. Protocols differ with respect to the allergen used, the mode of sensitisation and the number and timings of airway challenges. These differences are sometimes reflected by changes in the extent and duration of inflammation (compare [24^••] with [25^••]) [37], but can also result in mechanistic differences in the development of the disease (e.g. compare [18^••] with [19^••]) (Table 1

Prospects for therapeutic intervention

Animal data for blocking chemokines are compelling, and the prospect of targeting chemokine receptors on leukocytes is attractive because G-protein-coupled receptors are historically good targets. However, the perception that CCR3, CCR4 and CCR8 play a critical role in the selective recruitment of Th2 cells to sites of allergic inflammation has not been confirmed by in vivo studies with chemokine receptor KO mice. Further studies are necessary to determine whether these results are caused by

Conclusions

Mouse models have generated vast amounts of data regarding the role of specific chemokines in recruiting leukocytes to the lung after allergen challenge. However, the validity of these data depends on the ability of the model to represent the human disease. Further work is needed to determine how CCR3, CCR4 and CCR8 interact to mediate the recruitment of Th2 cells and eosinophils to the allergic lung, and to confirm these results in human studies. Although some studies appear contradictory,

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

•
of special interest
••
of outstanding interest

Acknowledgements

The authors are supported by the Wellcome Trust (Reference 057704 to Clare Lloyd and 058190 to Sara Rankin).

References (42)

Y. Yang et al.
Antigen-induced eosinophilic lung inflammation develops in mice deficient in chemokine eotaxin
Blood
(1998)
M. Kitaura et al.
Molecular cloning of a novel human CC chemokine (eotaxin-3) that is a functional ligand of CC chemokine receptor 3
J Biol Chem
(1999)
J.-A. Gonzalo et al.
Mouse eotaxin expression parallels eosinophil accumulation during lung allergic inflammation but it is not restricted to a Th2-type response
Immunity
(1996)
S. Romagnani
Cytokines and chemoattractants in allergic inflammation
Mol Immunol
(2002)
S.H. Oliveira et al.
Increased responsiveness of murine eosinophils to MIP-1beta (CCL4) and TCA-3 (CCL1) is mediated by their specific receptors, CCR5 and CCR8
J Leukoc Biol
(2002)
F. Sallusto et al.
Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells
Science
(1997)
R. Bonecchi et al.
Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s
J Exp Med
(1998)
Gonzalo J-A, Lloyd CM, Kremer L, Finger E, Martinez-A. C, Siegelman MH, Cybulsky MI, Gutierrez-Ramos J-C: Eosinophil...
Gonzalo J-A, Lloyd CM, Wen D, Albar JP, Wells TNC, Proudfoot A, Martinez-A C, Dorf M, Bjerke T, Coyle AJ,...
E.M. Campbell et al.
Temporal role of chemokines in a murine model of cockroach allergen-induced airway hyperreactivity and eosinophilia
J Immunol
(1998)

C.M. Lloyd et al.

CC Chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo

J Exp Med

(2000)

M.E. Rothenberg et al.

Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia

J Exp Med

(1997)

P.D. Ponath et al.

Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils

J Clin Invest

(1996)

J.R. White et al.

Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils

J Leukoc Biol

(1997)

N. Zimmermann et al.

Murine eotaxin-2: a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression

J Immunol

(2000)

A. Menzies-Gow et al.

Eosinophil chemokines and chemokine receptors: their role in eosinophil accumulation and activation in asthma and potential as therapeutic targets

J Asthma

(2001)

K. Watanabe et al.

Eotaxin-2 generation is differentially regulated by lipopolysaccharide and IL-4 in monocytes and macrophages

J Immunol

(2002)

S.L. Cuvelier et al.

Shear-dependent eosinophil transmigration on interleukin 4-stimulated endothelial cells: a role for endothelium-associated eotaxin-3

J Exp Med

(2001)

A.A. Humbles et al.

The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness

Proc Natl Acad Sci USA

(2002)

W. Ma et al.

CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation

J Clin Invest

(2002)

J.A. Gonzalo et al.

Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation

J Immunol

(1999)

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Le trafic des cellules immunitaires au sein de l’organisme est assuré par de petites protéines appelées chimiokines. Les leucocytes expriment à leur surface leurs récepteurs correspondant, qui, une fois liés aux chimiokines permettent la migration des cellules à travers les cellules endothéliales. En conditions basales ainsi que dans de multiples pathologies, la migration des cellules est une étape clé du système immunitaire. L’expression exagérée ou anormale de ces récepteurs de chimiokine dans l’allergie est ainsi un des facteurs essentiels dans le déclenchement de la réponse allergique. Beaucoup d’études se sont penchées sur l’importance des chimiokines et de leurs récepteurs dans les maladies allergiques comme l’asthme, les allergies alimentaires ou encore la dermatite atopique. Par ailleurs, le blocage des récepteurs par le biais d’antagoniste a permis de développer de nouvelles stratégies thérapeutiques, supprimant le recrutement des cellules lors de la réaction allergique. Dans cette revue, nous détaillerons donc les chimiokines et leurs récepteurs les plus importants dans les trois allergies citées et nous préciserons quels sont les antagonistes développés à ce jour contre les récepteurs de chimiokines.
Immune cell trafficking is orchestrated by a family of small proteins named chemokines and leucocytes express chemokine receptors on their surface. Once chemokines are attached to these receptors, they trigger transendothelial migration. During basal conditions as well in various diseases, leukocyte migration is a crucial step for the immune system. Excessive or inappropriate expression of chemokine receptors in allergy is thus one of the key factors, which trigger the allergic response. Consequently, many studies have been made on the importance of chemokines and their receptors in allergic diseases such as asthma, food allergy and atopic dermatitis. Moreover, as these receptors can easily be blocked by an antagonist, this has led to the development of new therapeutic approaches aimed at suppressing the recruitment of immune cells during an allergic reaction. In this review, we will detail which chemokines and which chemokine receptors are important in the three main allergic diseases mentioned above and describe the chemokine receptor antagonists, which have been developed to date.

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Chemokines in allergic airway disease

Abstract

Introduction

Section snippets

CCL11 and CCR3

CCL22, CCL17 and CCR4

CCL1 and CCR8

CXCL12 and CXCR4

Chemokine receptor expression after allergen challenge of atopic asthmatics

Chemokine receptor expression is dynamic in vivo

Relevance of mouse models to human disease

Prospects for therapeutic intervention

Conclusions

References and recommended reading

Acknowledgements

Blood

J Biol Chem

Immunity

Mol Immunol

J Leukoc Biol

Selective expression of the eotaxin receptor CCR3 by human T helper 2 cells

Science

Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s

J Exp Med

Temporal role of chemokines in a murine model of cockroach allergen-induced airway hyperreactivity and eosinophilia

J Immunol

CC Chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo

J Exp Med

Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia

J Exp Med

Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding and functional properties suggest a mechanism for the selective recruitment of eosinophils

J Clin Invest

Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils

J Leukoc Biol

Murine eotaxin-2: a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression

J Immunol

Eosinophil chemokines and chemokine receptors: their role in eosinophil accumulation and activation in asthma and potential as therapeutic targets

J Asthma

Eotaxin-2 generation is differentially regulated by lipopolysaccharide and IL-4 in monocytes and macrophages

J Immunol

Shear-dependent eosinophil transmigration on interleukin 4-stimulated endothelial cells: a role for endothelium-associated eotaxin-3

J Exp Med

The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness

Proc Natl Acad Sci USA

CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation

J Clin Invest

Mouse monocyte-derived chemokine is involved in airway hyperreactivity and lung inflammation

J Immunol