Leukocyte infiltration of the lung is a characteristic feature of allergic asthma and it is thought that these cells are selectively recruited by chemokines. Extensive research has confirmed that chemokine receptors are expressed on the main cell types involved in asthma, including eosinophils, T helper type 2 cells, mast cells and even neutrophils. Moreover, animal experiments have outlined a functional role for these receptors and their ligands. Chemokines signal via seven-transmembrane spanning G-protein coupled receptors, which are favored targets of the pharmaceutical industry due to the possibility of designing small-molecule inhibitors. In fact, this family represents the first group of cytokines where small-molecule inhibitors have been designed. However, the search for efficient antagonists of chemokine/chemokine receptors has not been easy; a particular feature of the chemokine system is the number of molecules with overlapping functions and binding specificities, as well as the difficulty in reconciling the in vivo biologic functional validation of chemokines in rodent models with the development of antagonists which bind the human receptor, because of the lack of species cross-reactivity. The chemokines and their receptors that are active during allergic reactions are reviewed. Possible points of interaction that may be a target for development of new therapies, as well as the progress to date in developing inhibitors of key chemokine receptors for asthma therapy, are also discussed.
One of the hallmarks of allergic asthma is accumulation of inflammatory leukocytes in the lung following allergen challenge. These inflammatory infiltrates are heterogeneous and are generally composed of eosinophils and lymphocytes as well as monocytes and mast cells. The size and nature of infiltrates has been shown to relate to disease severity, and the pathophysiologic features of the asthmatic reaction are thought to occur as a direct result of these leukocytes. The chemokine family has been shown to play a pivotal role in this selective recruitment of inflammatory leukocytes to the airways, and as such the manipulation of this pathway represents a prospective therapeutic strategy to reduce inflammation and abrogate asthma symptoms.
Chemokines belong to a family of specialized cytokines whose primary function is to regulate the trafficking of leukocytes. All of the family members are small secreted heparin-binding proteins distinguishable from classic chemoattractant molecules such as bacterial derived N-formyl peptides, complement fragment peptides C3a and C5a, and lipid molecules such as leukotriene B4 and platelet activating factor, on the basis of shared structural similarities. Chemokines have four conserved cysteine residues that form disulfide bonds that are critical for the tertiary structures of the proteins. There are four subclasses according to the position of the first two cysteines. The CC chemokines have adjacent cysteines and incorporate CCL1 through CCL28. In contrast, CXC chemokines (CXCL1 through CXCL16) have cysteines separated by one amino acid. Members of the C class (XCL1 and XCL2) have two cysteines, not four, while the only member of the CX3C subclass, CX3CL1, has three amino acids between the first two cysteines with a mucin stalk at the N-terminal end. The general structure of chemokines includes a short amino-terminal domain preceding the first cysteine, a backbone made of β-strands and the connecting loops found between the second and fourth cysteines, and a carboxy-terminal α-helix of 20–30 amino acids.
2. Chemokine Receptors
The specific biologic effects of chemokines are mediated via interactions with heterotrimeric seven-transmembrane G-protein coupled receptors (GPCRs) expressed predominantly on leukocytes. Chemokine receptors have seven α-helical transmembrane domains, with three intracellular and three extracellular connecting loops and a disulfide bond linking highly conserved cysteines in extracellular loops 1 and 2. The N-terminus and the third intracellular loop are thought to be essential for specific binding of chemokines. Chemokine receptors couple to heterotrimeric G-proteins through the C-terminus segment and possibly through the third intracellular loop (reviewed by Thelen).
The chemokine receptors are also distributed among specific families. Chemokine receptors CXCR1 to CXCR6 bind the CXC family of chemokines, whereas the CC family bind to receptors CCR1 to CCR10. XCR1 and CX3CR1 bind members of the C and CX3C subfamilies, respectively. In addition, virally encoded chemokine receptors have been described, and are thought to be a mechanism of viral evasion from the immune system.
3. Cell Recruitment in Asthma
Allergen-induced recruitment of leukocytes to the lung is thought to be a major factor in the development of the pathophysiologic symptoms of asthma.
Eosinophils: These granulocytes form the major component of inflammatory infiltrates. The molecules they secrete on degranulation are thought to be important for the tissue damage that leads to the disruption of the bronchial epithelium, enhanced airway hyperresponsiveness (AHR) and bronchial obstruction. Eosinophils have been located in the submucosa as early as 6 hours after local allergen challenge of mild atopic patients.By 24 hours the majority of these eosinophils have migrated through the bronchial epithelium into the airways where they can be collected during bronchoalveolar lavage (BAL).
T cells: T cells of the T helper type 2 (Th2) subset are thought to be critical in controlling allergic reactions, although they are present in fewer numbers than eosinophils. Th2 cells secrete a range of mediators thought to initiate and magnify allergic responses, including the cytokines interleukin (IL)-4, IL-5 and IL-13. They are present in biopsies from allergic patients, and expression of Th2 cytokines is increased in patients after allergen challenge.Moreover, in vivo depletion experiments have shown that blocking CD4 or Th2 function,[5,6]or neutralizing key Th2 cytokines, abrogates pulmonary eosinophilia and AHR.
Mast cells: Mast cells are selectively located within the smooth muscle bundles and submucosal glands in atopic patients with asthma, and are thought to contribute to the airway dysfunction.Mast cells can release a range of mediators that contribute to pathology, including acute phase proteins as well as cytokines and chemokines.
Neutrophils: Although the primary granulocyte recruited to the lungs during allergic inflammation is the eosinophil, there is increasing evidence that neutrophils are present in the allergic lung, particularly during severe asthma. Data suggest that during severe asthma neutrophils persist in bronchi and could in part be responsible for the epithelial damage, the extensive mucus plug, and the abnormalities of epithelial and endothelial permeability which are associated with acute severe asthma.
Table I summarizes the chemokines and their receptors that induce migration of key leukocytes to the allergic lung.
4. Chemokine Function in Asthma
The main function of chemokines is to promote directed migration of cells. A large number of studies have analyzed expression of chemokines and their receptors in the lung during allergic reactions.[9,10]Immunohistochemical analyses of biopsy sections and lavage cells from patients, post allergen challenge, have provided a picture of the expression patterns of key chemokines and their receptors. Coupled with time course studies from animal models, it has been shown that the pattern of chemokine expression changes during the progression of disease. Moreover, the temporal and spatial expression of chemokines and their receptors dictates the recruitment of different leukocyte populations. The location, range and distribution of putative chemotactic gradients depend on the spatial location of the cell secreting the specific chemokine. Thus, mapping the chemotactic gradients and their patterns of expression are essential in understanding the roles of particular chemokines in the asthmatic process, as well as in planning novel therapeutic strategies based on those chemokines.
In addition to their role in cell recruitment, chemokines exhibit other functions that are critical in the generation of a robust allergic response. Chemokines have been shown to synergize with cytokines to exert maximal biologic effect. A prime example of this is the relationship between IL-5 and eotaxin to promote mobilization of eosinophils from the bone marrow and recruitment to the lung following allergen challenge.In this model it has been postulated that IL-5 and eotaxin act in a coordinated manner, with IL-5 mobilizing eosinophils from the bone marrow and eotaxin directing their local recruitment into the tissue. Other chemokines have also been shown to be important for the polarization of the immune response. For example, monocyte chemoattractant protein (MCP)-1 is important in the recruitment of monocytes and T cells to inflammatory reactions. However, experiments have also shown that MCP-1 can drive differentiation of naïve T cells towards an IL-4 producing Th2 cell. Moreover, mice that lack MCP-1 are unable to mount efficient Th2 responses.These experiments suggest that MCP-1 has an important role in driving the allergic response, possibly in the primary sensitization process.
As discussed above, the primary role of chemokines is thought to be the ability to promote recruitment of inflammatory cells to sites of inflammation. However, evidence also suggests that some chemokines might be involved in the resolution of injury. The receptor D6 has been shown to act as a decoy receptor for other chemokines in a model of cutaneous inflammation.This study highlighted the role of the D6 chemokine receptor as a regulator of cutaneous inflammation and raised the possibility that such control mechanisms might also exist during allergic inflammation of the lung. As such, strategies to maximize the activity of the D6 chemokine receptor would be of benefit in asthma.
The exacerbation of asthmatic responses is most frequently caused by pulmonary viral infections such as rhinovirus, influenza virus, adenovirus or respiratory syncytial virus (RSV). The local production of chemokines appears to be central to the severity of the asthmatic response. RSV infection seems to initiate extremely high levels of many chemokines including RANTES (Regulated upon Activation Normal T cells Expressed and Secreted)/CCL5, MCP-1/CCL2 as well as the CXC chemokine IL-8/CXCL8.[14,15]The production of chemokines during RSV infection has more recently been examined using mouse models of infection; interestingly, when CXCR2 function was blocked in mice infected with RSV, both goblet cell metaplasia/hyperplasia and mucus protein were significantly attenuated.
The development of goblet cell metaplasia/hyperplasia and mucus production is one of the hallmarks of chronic asthmatic responses that lead to the long-term dysfunction of airway physiology and contribute significantly to the pathophysiologic changes in asthma. Members of the CXC chemokine family have been associated with mucus overproduction and, interestingly, a strong correlation has been drawn between over expression of CXCL8 and increased production of mucus.Recent in vivo studies using CXCR2-/- mice have demonstrated significant attenuation of the disease in a chronic Aspergillus fumigatus model.
5. Prospects for Intervention
Chemokines are involved in multiple aspects of the pathologic response to allergen and this makes them attractive therapeutic targets. Experiments in animal models have shown that inhibition of cell recruitment after allergen challenge abrogates the key physiologic features of eosinophilia and AHR. The chemokine system offers multiple points for putative intervention, in order to design novel strategies for therapy. The most direct is to interfere with chemokine binding to its cognate receptor. The success of small-molecule inhibitors of GPCRs in the treatment of various other diseases has led the pharmaceutical and biotechnology industries to investigate the action of small-molecule inhibitors of chemokine receptors. Based on this strategy, several methods of antagonizing chemokine receptors are being investigated using: (i) small-molecule antagonists; (ii) modified chemokines; (iii) neutralizing antibodies; or (iv) viral antagonists.
5.1 Small-Molecule Antagonists
Chemokine receptors expressed on eosinophils are of particular interest for targeting because they represent the most prominent infiltrating leukocyte. CCR3 is an obvious choice since it is expressed not only on eosinophils, but also on Th2 cells, both of which are critical in the development of the asthmatic response.[19–21]A range of chemokines signal via CCR3, including the eotaxin family, as well as RANTES, MCP-4 and MCP-3, all of which have been documented to be up-regulated in asthma.Signaling through CCR1 and CCR3 has been blocked successfully in vitro using a single compound (UCB 35625),however in vivo data are not available as yet. A number of other therapeutic agents targeting CCR3 are in the pipeline from the major pharmaceutical companies, but at present the most advanced data have come from compound DPC168 which completed phase I studies for asthma and allergic rhinitis.Other CCR3 antagonists have been reported to be effective in mouse and non-human primate models of allergic lung inflammation.GW 766994 is a low molecular weight compound in phase II trials for asthma and allergic rhinitis which would hopefully provide the final proof of principle in man (table II). However, no clinical data for these compounds have been reported. One reason for the delay in development of CCR3 antagonists may stem from nervousness in the industry after the failure of therapies such as anti-IL-5 antibody treatment to affect eosinophil recruitment after allergen challenge,as well as an indication that eosinophils may not control airway hyperresponsiveness as evidenced in a mouse model.However, further clinical trials are needed, perhaps with combination therapy designed to target CCR3 ligands in conjunction with IL-5, before the eosinophil can be de-prioritized as a candidate target in asthma. This is particularly important in the light of data which indicate that eosinophils play an important role in other aspects of the asthmatic reaction, such as airway remodeling.[27,28]
Another area of investigation is the suppression of Th2 responses, since this population of effector cells is thought to be responsible for the initial development and subsequent escalation of the allergic response. Receptors on Th2 cells include CCR3, CCR4 and CCR8. To date, there are no compounds that selectively target chemokine receptors, but these receptors are currently the subject of intense investigation. Neutralization of either TARC (intervention of thymus and activation-regulated chemokine; CCL17) or MDC (monocyte-derived chemokine; CCL-22) using antibodies has resulted in reduced airway inflammation and AHR in mice.[29,30]However, in marked contrast, CCR4-deficient mice did not show any change in either cell recruitment or reduction in AHR.In addition, CCR4 ligands are up-regulated in the airways of atopic patients following allergen challenge.Thus, the utility of developing CCR4 antagonists for asthma is controversial. Bristol-Myers Squibb and ICOS have recently reported small molecular weight CCR4 receptor antagonists as potential therapeutic agents for allergic disease (table II).[33,34]To date, there are no compounds that selectively target CCR8, even though initial findings demonstrated that the disruption of the CCR8 gene resulted in a marked reduction of the allergen-induced airway hyperresponsiveness, suggesting that CCR8 is involved in the recruitment of lymphocytes that could lead to airway obstruction and increased airway damage; subsequent publications suggest that CCR8 alone is not essential for the development of allergic airway disease.[35–37]It is interesting to note that Th1-related chemokines are also up-regulated in the airways during allergic reactions[38,39]with the CXCR3 ligand, CXCL10, being found in the BAL fluid of patients. This might induce the recruitment of Th1 cells or mast cells since the CXCR3/CXCL10 axis has been shown to mediate mast cell migration within human asthmatic airway smooth muscle.Several inhibitors of CXCR3 have been described,but have not as yet been tested in vivo during allergic airway disease.
One other potentially important chemokine axis that has been targeted during allergic inflammation is that of CXCR4 and its ligand CXCL12. CXCR4 has been found to be expressed on Th2 cells, but not exclusively, as it is also found on a wide range of other cells including CD34+ stem cells, B cells and monocytes. However, neutralization of CXCR4 using a blocking antibody reduces airway inflammation.Due to the potential involvement of CXCR4 in HIV infection, small-molecule antagonists for CXCR4 have been the subject of intense investigation. Of interest is a study where one of these antagonists (AMD 3100) significantly reduced airway hyperreactivity, peribronchial eosinophilia, and overall inflammatory responses in a mouse model of asthma.This study represents the first example of a small-molecule antagonist successfully attenuating an allergic reaction in vivo.
5.2 Modified Chemokines
Modified chemokines and N-terminal peptides can be engineered to allow them to retain binding specificity and affinity to a receptor while blocking intracellular signaling and therefore function. A modified version of RANTES, whereby an additional methionine residue was added to the N-terminus,decreased both cellular inflammation and AHR in an in vivo mouse model of allergic pulmonary disease.[5,45]Similarly, addition of an aminooxypentane residue at the N-terminus of RANTES (AOP-RANTES) has been shown to inhibit HIV-1 infectivity in macrophages and lymphocytes.A CCR3 antagonist termed CKβ7 has been generated by an amino-terminal alanine-methionine swap of macrophage inflammatory protein 4.Whereas Met-RANTES inhibits eosinophil effector function through antagonizing CCR1 and CCR3, CKβ7 specifically antagonizes CCR3. CKβ7 is a more potent CCR3 antagonist than Met-RANTES and prevents signaling through CCR3 at concentrations of 1 nmol/L. However, the success of modified chemokines or N-terminal peptides as antagonists depends mostly on their capacity to fully occupy the chemokine receptor/s at nanomolar concentrations, competing with the natural ligand/s binding and thus blocking signaling. One of the advantages of using a modified ligand is that most of the receptors used by that ligand can be blocked, or partially blocked, by a single antagonist.[48,49]
5.3 Therapeutic Antibodies
Generation of specific monoclonal antibodies against chemokines or their receptors represents another strategy to modify chemokine function. A range of in vivo studies with mouse models of allergic disease have demonstrated the benefits of blocking chemokines(reviewed by Homey and Zlotnik) but the range of chemokine functions, particularly those in lymphocyte homeostasis, suggests that targeting receptors may be a more effective therapeutic prospect. A neutralizing monoclonal antibody against CCR3 blocks chemotaxis and calcium flux induced by all CCR3 ligands in human eosinophils in vitro.Moreover, a neutralizing monoclonal anti-CCR3 antibody was shown to inhibit eosinophil recruitment to the lung and the associated airway hyperreactivity in the mouse, implying that a similar treatment strategy might be beneficial for patients with asthma.The most advanced anti-chemokine antibody for the treatment of allergy/asthma is bertilimumab (CAT213), a human IgG4 monoclonal antibody against eotaxin, which effectively and specifically inhibits its function, and is under development by Cambridge Antibody Technology (CAT) [table II]. Phase I/IIa clinical studies have shown that bertilimumab was well tolerated with no serious adverse events reported, and the compound is currently in phase II clinical trials for allergic rhinitis and in preclinical investigation for asthma.
5.4 Viral Antagonists
Another potential source of chemokine antagonists comes from the observation that many viruses use chemokine antagonists to subvert immune responses.Chemokine homologs such as vMIP-II were probably pirated by viruses for broad antagonistic activity. VMIP-II is encoded by Kaposi sarcoma herpes virus HHV8.This viral chemokine antagonizes many of the Th1-associated receptors such as CCR1, CCR2 and CCR5, but stimulates Th2-associated receptors such as CCR3 or CCR8.Other viruses use membrane-expressed chemokine receptor homologs, such as US28, a protein encoded by cytomegalovirus, to soak up chemokines to suppress host responses.A noteworthy feature of most viral chemokines or chemokine binding proteins is their broad chemokine or receptor-binding capabilities, which suggests that viruses need to circumvent chemokine redundancy for effective immune subversion. As yet there are no examples of successful reduction in airway pathophysiology with any of these viral chemokine antagonists.
It is also possible that preventing chemokine function might be achievable by interfering at other points of the chemokine/receptor interaction. Chemokine activity is tightly regulated, in that activation of the endothelium by pro-inflammatory cytokines results in the secretion of chemokines and their presentation on the endothelial surface by glycosaminoglycans (GAGs). In this way chemokines are anchored to maximize interaction with inflammatory leukocytes bearing their cognate receptor. In addition, this property is thought to be important for the spatial distribution of chemokines. Recent experiments have shown that chemokine interaction with GAGs is critical to elicit cell recruitment in vivo.Moreover, differential GAG binding patterns exert a sophisticated level of control of chemokine presentation and or activation both temporally and spatially – therefore intervention with this process is likely to be successful in down-regulating chemokine function.
5.5 Intracellular Signaling Pathways
An alternative strategy to minimize chemokine function would be to interfere with chemokine activated intracellular signaling pathways. Binding of a chemokine with its 7 transmembrane spanning receptor initiates a range of different intracellular signaling molecules.Chemokine receptors are coupled to heterotrimeric G proteins and when chemokine is bound to the receptor the Gαβγ subunits are dissociated and are able to activate a variety of intracellular enzymes including phospholipid kinases, lipases and guanine nucleotide-exchange factors. These enzymes regulate the phosphorylation and release of second messengers. One of the key targets thought to be involved in the chemokine signaling pathways is phosphoinositide 3-kinase. These are a family of enzymes that lead to the generation of lipid second messengers that regulate a number of cellular events. The PI3Kγ isoform is involved in neutrophil recruitment and activation and knockout of the PI3Kγ gene results in impaired mast cell, macrophage and T lymphocyte development and function.This suggests that selective PI3Kγ inhibitors may have relevant anti-inflammatory activity in asthma, and thus the Class I PI3K are at present a major goal for several pharmaceutical companies. The search for a specific and selective inhibitor for the PI3Kγ isoform is ongoing.
Drugs designed to interfere with the intracellular signaling initiated by chemokine binding are currently being investigated in respiratory disease.In particular, inhibitors of p38 mitogen-activated protein kinase/extracellular-signal-regulated kinase which inhibit the synthesis of cytokine and chemokines are now in phase II development (e.g. SB 239063).[62,63]Whether this new class of anti-inflammatory drugs will be safe in the long-term studies remains to be established. Many transcription factors are involved in the expression of inflammatory genes in asthmatic airways. Evidence suggests that chemokines can induce tyrosine phosphorylation of their receptors independent of Gαβγ, with subsequent receptor dimerization and recruitment of JAK (Janus kinase) and STAT (signal transduction and activators of transcription), thus providing a direct link to transcriptional regulation.[64,65]Inhibitors of nuclear factor-κB pathway such as the selective inhibitors of κB kinase 2 which are currently under development may in future show utility in asthma by inhibiting chemokine-induced activation of transcription factors.
6. Potential Problems
One of the potential pitfalls in designing strategies to limit interactions of chemokines with their receptors is the large number of receptors and endogenous ligands and their overlapping specificities for each other and for leukocyte subtypes. Some receptors bind only one chemokine (for example CXCR1 binds only CXCL8), while others are shared by multiple ligands (such as CCR1 which binds CCL5, CCL7 and CCL8). In addition, another receptor known as DARC (Duffy antigen/receptor for chemokines) is truly promiscuous and binds both CC and CXC chemokines. The other problem is the potential of redundancy in the chemokine system, since so many chemokines have overlapping functions. However, detailed time course studies in animal and human allergen challenge models have shown that chemokine production in vivo is organized and coordinated.These studies argue against redundancy in the chemokine system because individual chemokines and receptors seem to influence different stages of particular pathways in the development of pathology. Thus, chemokines are thought to function in a tightly controlled manner with particular chemokines operating at key stages of the response.
Another major problem in the development of chemokine therapeutic agents is the lack of cross-reactivity between species. The vast majority of proof-of-concept biology and target validation has been undertaken in mouse or rat models, whereas inhibitors are being developed for human receptors. It is then difficult to test the resulting leads in animal models for efficacy studies. The molecular basis of such species selectivity is not understood, and does not occur for all compounds. Humans have a more diverse array of chemokine ligands than mice and the expression patterns of chemokine and chemokine receptors are different in rodents. A good example of this is CCR1, which is highly expressed on rodent neutrophils and weakly on human neutrophils. The other major obstacle encountered in the transition of potent compounds from in vitro to in vivo has been their pharmacokinetic properties; for example, whether these agents will stay at the site of action for long enough and in high enough concentrations to be effective. Whether these compounds proceed to the clinic will depend largely on their therapeutic index, how well they are tolerated, and on their toxicity profile. Clearly, the latter is a must, given that many of the potential disease applications for chemokine-receptor antagonists will be for chronic diseases.
The identification and characterization of various chemokines and their receptors expressed during the progression of asthmatic disease has led to the concept that although a number of targets have been suggested, specific delineation of receptors relevant to the disease needs to be accomplished. There is a great need for new therapeutic agents to target all aspects of asthma. An advance in therapy would be the development of more specific anti-asthma drugs that lack adverse effects. Blocking a single mediator or cytokine is unlikely to be as effective, as such treatments are too specific. Therefore, alternative strategies from considering single chemokine receptor antagonists would be to consider potential antagonists targeting multiple chemokine receptors (CCR3, 4 and 8) or exploring chemokine signaling pathways to identify disease-relevant targets central to inflammatory disorders in which cell migration plays a critical role.
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CML is a Wellcome Senior Research Fellow and her work is funded by the Wellcome Trust (Ref 05774); ZB is employed by Novartis. No sources of funding were used in the preparation of this article.
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Lloyd, C.M., Brown, Z. Chemokine Receptors. Treat Respir Med 5, 159–166 (2006). https://doi.org/10.2165/00151829-200605030-00002
- Respiratory Syncytial Virus
- Allergic Rhinitis
- Chemokine Receptor
- Respiratory Syncytial Virus Infection