PERSPECTIVE
Why So Many CCR3 Ligands? |
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
receptor (
|
One of the perplexing questions in chemokine biology is why is there such redundancy among the ligands and why are many ligands promiscuous with respect to receptor activation? More specifically, why are there so many ligands that bind to and activate CCR3? While it is possible that CCR3 activation is essential for human life, the viability of CCR3-deficient mice provides potent evidence against this concept. A seemingly more reasonable explanation is that ligand duplicity allows differential regulation of CCR3 activation by alternative stimuli or at different tissue loci. Ligand duplicity therefore allows a stimulus-dependent intensity, duration, or tissue distribution of ligands that recruit CCR3 receptor-bearing cells. The local activity of alternative ligands is also affected by differences in the efficiency with which they are presented to CCR3-bearing cells by tissue proteoglycans, including those on endothelial cells (22). These differences allow for a robust repertoire of chemotactic gradient tissue responses and patterns of inflammatory cell recruitment. Receptor promiscuity (Table 1) allows alternative ligands to activate different panels of chemokine receptors and allows for selectivity of the cellular response to alternative environmental stimuli. In addition to a diverse role in mediating airway inflammation, there is increasing evidence that the CCR3 receptor-ligand system may have a role in the migration of structural as opposed to inflammatory cells during development and possibly in tissue responses to injury (23).
The tissue recruitment of the cells which mediate allergic inflammation is a coordinated process that involves the
expression of groups of chemokines at specific tissue microenvironmental loci with a specific kinetic and temporal
sequence. It is this spatial and temporal regulation that allows for diversity of the allergic response. It is now clear
that distinct combinations of CCR3-active 
-chemokines
regulate the recruitment and retention of eosinophils in
different tissues and allergic disease categories. Studies in
eotaxin-deficient mice (24) imply that eotaxin is important
in the early recruitment of eosinophils into the lung after
allergen challenge. Moreover, eotaxin is known to be induced during the early phase of eosinophil recruitment
into the lungs of allergen-challenged atopic asthmatics (25,
26). Interestingly, eotaxin-3 mRNA, but not eotaxin or eotaxin-2 mRNA, is upregulated in the lung 24 h after allergen challenge in humans with asthma, implying that this
-chemokine, acting through CCR3, is responsible for the
continuing eosinophil recruitment observed during the late phase reaction (27). In support of this concept, the importance of coordinated activation of groups of chemokines for pulmonary eosinophil recruitment and altered
physiologic responses has been elegantly demonstrated
in the murine allergen challenge model (28). Allergen-induced chemokine expression patterns in the lung are divergent from those observed in the skin of allergen-challenged atopic subjects. While eotaxin is associated with the
early recruitment of eosinophils in both tissues, expression
of eotaxin-2 and MCP-4 correlates with the late phase of
eosinophil recruitment in the skin (29). In the gastrointestinal tract, eotaxin is expressed constitutively, thereby
modulating tissue eosinophil presence at this mucosal surface with a distinct temporal pattern of eotaxin expression
(30). Taken together, these observations imply that distinct groups of chemokines, each expressed with unique
temporal and tissue-specific characteristics, are responsible for the various forms of allergic inflammation observed in atopic individuals. Elucidating the role of this
novel LPS-inducible CCR3 ligand may improve our understanding of the orchestration of allergic inflammation, which allows clinical expression of the atopic diseases.
Associations among LPS, allergy, and airway inflammation have led to great interest in elucidating the pathways by which LPS influences allergic processes. The effects of LPS on the allergic phenotype appear to be dependent on the timing of exposure in the process of allergic sensitization. Evidence from an animal model (31) and a cross-sectional study of infants has suggested that exposure early in this process may impede the development of atopy (32). Exposure after sensitization appears to be associated with asthma symptoms in infants, children, and adults, including those with occupational exposure to LPS (33). One of the exciting aspects of this report is the possibility that elucidating the role of this LPS-inducible CCR3 ligand may allow us a better understanding of the com-plex mechanistic links between LPS and the allergic diseases.
 |
Footnotes |
|---|
Address correspondence to: Craig M. Lilly, M.D., Pulmonary and Critical Care Division, Brigham and Women's Hospital, 75 Francis Street, Tower 4, Boston, MA 02115. E-mail: clilly{at}partners.org
(Received in original form October 31, 2001).
Abbreviations: interleukin, IL; lipopolysaccharide, LPS; vaccinia virus 35 kD pan-chemokine binding protein, vCKBP.
| |
References |
|---|
1. Mackay, C. R.. 2001. Chemokines: immunology's high impact factors. Nat. Immunol. 2: 95-101 . [Medline]
2.
Luster, A. D..
1998.
Chemokines: chemotactic cytokines that mediate inflammation.
N. Engl. J. Med.
338:
436-445
3.
Sabroe, I.,
A. Hartnell,
L. A. Jopling,
S. Bel,
P. D. Ponath,
J. E. Pease,
P. D. Collins, and
T. J. Williams.
1999.
Differential regulation of eosinophil chemokine signaling via CCR3 and non-CCR3 pathways.
J. Immunol.
162:
2946-2955
4. Heath, H., S. Qin, P. Rao, L. Wu, G. LaRosa, N. Kassam, P. D. Ponath, and C. R. Mackay. 1997. Chemokine receptor usage by human eosinophils: the importance of CCR3 demonstrated using an antagonistic monoclonal antibody. J. Clin. Invest. 99: 178-184 [Medline].
5.
Penido, C.,
H. C. Castro-Faria-Neto,
A. Vieira-de-Abreu,
R. T. Figueiredo,
A. Pelled,
M. A. Martins,
P. J. Jose,
T. J. Williams, and
P. T. Bozza.
2001.
LPS induces eosinophil migration via CCR3 signaling through a mechanism independent of RANTES and eotaxin.
Am. J. Respir. Cell Mol. Biol
25:
707-716
6.
Alcami, A.,
J. A. Symons,
P. D. Collins,
T. J. Williams, and
G. L. Smith.
1998.
Blockade of chemokine activity by a soluble chemokine binding protein from vaccinia virus.
J. Immunol.
160:
624-633
7. Lalani, A. S., and G. McFadden. 1999. Evasion and exploitation of chemokines by viruses. Cytokine Growth Factor Rev. 10: 219-233 . [Medline]
8. Murphy, P. M.. 2001. Viral exploitation and subversion of the immune system through chemokine mimicry. Nat. Immunol. 2: 116-122 . [Medline]
9.
Dabbagh, K.,
Y. Xiao,
C. Smith,
P. Stepick-Biek,
S. G. Kim,
W. J. Lamm,
D. H. Liggitt, and
D. B. Lewis.
2000.
Local blockade of allergic airway hyperreactivity and inflammation by the poxvirus-derived pan-CC-chemokine inhibitor vCCI.
J. Immunol.
165:
3418-3422
10.
Foster, P. S.,
S. P. Hogan,
A. J. Ramsay,
K. I. Matthaei, and
I. G. Young.
1996.
Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model.
J. Exp. Med.
183:
195-201
11. Pope, S., and M.., E. B. Brandt, A. Mishra, S. P. Hogan, N. Zimmermann, K. I. Matthaei, P. S. Foster, and M. E. Rothenberg. 2001. IL-13 induces eosinophil recruitment into the lung by an IL-5- andeotaxin-dependent mechanism. J. Allergy Clin. Immunol. 108: 594-601 [Medline].
12.
Daugherty, B. L.,
S. J. Siciliano,
J. A. DeMartino,
L. Malkowitz,
A. Sirotina, and
M. S. Springer.
1996.
Cloning, expression, and characterization of the
human eosinophil eotaxin receptor.
J. Exp. Med.
183:
2349-2354
13.
Ponath, P. D.,
S. Qin,
T. W. Post,
J. Wang,
L. Wu,
N. P. Gerard,
W. Newman,
C. Gerard, and
C. R. Mackay.
1996.
Molecular cloning and characterization of a human eotaxin receptor expressed selectively on eosinophils.
J. Exp. Med.
183:
2437-2448
14.
Forssmann, U.,
M. Uguccioni,
P. Loetscher,
C. A. Dahinden,
H. Langen,
M. Thelen, and
M. Baggiolini.
1997.
Eotaxin-2, a novel CC chemokine that is
selective for the chemokine receptor CCR3, and acts like eotaxin on human eosinophil and basophil leukocytes.
J. Exp. Med.
185:
2171-2176
15. White, J. R., C. Imburgia, E. Dul, E. Appelbaum, K. O'Donnell, D. J. O'Shannessy, M. Brawner, J. Fornwald, J. Adamou, N. A. Elshourbagy, K. Kaiser, J. J. Foley, D. B. Schmidt, K. Johanson, C. Macphee, K. Moores, D. McNulty, G. F. Scott, R. P. Schleimer, and H. M. Sarau. 1997. Cloning and functional characterization of a novel human CC chemokine that binds to the CCR3 receptor and activates human eosinophils. J. Leukoc. Biol. 62: 667-675 [Abstract].
16. Elsner, J., H. Petering, C. Kluthe, D. Kimmig, R. Smolarski, P. Ponath, and A. Kapp. 1998. Eotaxin-2 activates chemotaxis-related events and release of reactive oxygen species via pertussis toxin-sensitive G proteins in human eosinophils. Eur. J. Immunol. 28: 2152-2158 [Medline].
17.
Shinkai, A.,
H. Yoshisue,
M. Koike,
E. Shoji,
S. Nakagawa,
A. Saito,
T. Takeda,
S. Imabeppu,
Y. Kato,
N. Hanai,
H. Anazawa,
T. Kuga, and
T. Nishi.
1999.
A novel human CC chemokine, eotaxin-3, which is expressed
in IL-4- stimulated vascular endothelial cells, exhibits potent activity toward eosinophils.
J. Immunol.
163:
1602-1610
18.
Kitaura, M.,
N. Suzuki,
T. Imai,
S. Takagi,
R. Suzuki,
T. Nakajima,
K. Hirai,
H. Nomiyama, and
O. Yoshie.
1999.
Molecular cloning of a novel human
CC chemokine (Eotaxin-3) that is a functional ligand of CC chemokine receptor 3.
J. Biol. Chem.
274:
27975-27980
19. Coulin, F., C. A. Power, S. Alouani, M. C. Peitsch, J. M. Schroeder, M. Moshizuki, I. Clark-Lewis, and T. N. Wells. 1997. Characterisation of macrophage inflammatory protein-5/human CC cytokine- 2, a member of the macrophage-inflammatory-protein family of chemokines. Eur. J. Biochem. 248: 507-515 [Medline].
20.
Pan, J.,
E. J. Kunkel,
U. Gosslar,
N. Lazarus,
P. Langdon,
K. Broadwell,
M. A. Vierra,
M. C. Genovese,
E. C. Butcher, and
D. Soler.
2000.
A novel
chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in
mucosal tissues.
J. Immunol.
165:
2943-2949
21.
Heinemann, A.,
A. Hartnell,
V. E. Stubbs,
K. Murakami,
D. Soler,
G. LaRosa,
P. W. Askenase,
T. J. Williams, and
I. Sabroe.
2000.
Basophil responses to chemokines are regulated by both sequential and cooperative
receptor signaling.
J. Immunol.
165:
7224-7233
22. Kuschert, G. S., F. Coulin, C. A. Power, A. E. Proudfoot, R. E. Hubbard, A. J. Hoogewerf, and T. N. Wells. 1999. Glycosaminoglycans interact selectively with chemokines and modulate receptor binding and cellular responses. Biochemistry 38: 12959-12968 [Medline].
23. Mennicken, F., R. Maki, E. B. de Souza, and R. Quirion. 1999. Chemokines and chemokine receptors in the CNS: a possible role in neuroinflammation and patterning. Trends Pharmacol. Sci. 20: 73-78 [Medline].
24.
Rothenberg, M. E.,
J. A. MacLean,
E. Pearlman,
A. D. Luster, and
P. Leder.
1997.
Targeted disruption of the chemokine eotaxin partially reduces
antigen-induced tissue eosinophilia.
J. Exp. Med.
185:
785-790
25.
Lilly, C. M.,
H. Nakamura,
O. I. Belostotsky,
K. J. Haley,
E. A. Garcia-Zepeda,
A. D. Luster, and
E. Israel.
2001.
Eotaxin expression after segmental allergen challenge in subjects with atopic asthma.
Am. J. Respir.
Crit. Care Med.
163:
1669-1675
26. Brown, J. R., J. Kleimberg, M. Marini, G. Sun, A. Bellini, and S. Mattoli. 1998. Kinetics of eotaxin expression and its relationship to eosinophil accumulation and activation in bronchial biopsies and bronchoalveolar lavage (BAL) of asthmatic patients after allergen inhalation. Clin. Exp. Immunol. 114: 137-146 [Medline].
27.
Berkman, N.,
S. Ohnona,
F. K. Chung, and
R. Breuer.
2001.
Eotaxin-3 but
not eotaxin gene expression is upregulated in asthmatics 24 hours after allergen challenge.
Am. J. Respir. Cell Mol. Biol.
24:
682-687
28.
Gonzalo, J. A.,
C. M. Lloyd,
D. Wen,
J. P. Albar,
T. N. Wells,
A. Proudfoot,
C. Martinez, and
-A, M. Dorf, T. Bjerke, A. J. Coyle, and J. C. Gutierrez-
Ramos.
1998.
The coordinated action of CC chemokines in the lung orchestrates allergic inflammation and airway hyperresponsiveness.
J. Exp.
Med.
188:
157-167
29.
Ying, S.,
D. S. Robinson,
Q. Meng,
L. T. Barata,
A. R. McEuen,
M. G. Buckley,
A. F. Walls,
P. W. Askenase, and
A. B. Kay.
1999.
C-C chemokines in allergen-induced late-phase cutaneous responses in atopic subjects: association of eotaxin with early 6-hour eosinophils, and of eotaxin-2
and monocyte chemoattractant protein-4 with the later 24-hour tissue eosinophilia, and relationship to basophils and other C- C chemokines
(monocyte chemoattractant protein-3 and RANTES).
J. Immunol.
163:
3976-3984
30.
Matthews, A. N.,
D. S. Friend,
N. Zimmermann,
M. N. Sarafi,
A. D. Luster,
E. Pearlman,
S. E. Wert, and
M. E. Rothenberg.
1998.
Eotaxin is required
for the baseline level of tissue eosinophils.
Proc. Natl. Acad. Sci. USA
95:
6273-6278
31.
Tulic, M. K.,
J. L. Wale,
P. G. Holt, and
P. D. Sly.
2000.
Modification of the
inflammatory response to allergen challenge after exposure to bacterial lipopolysaccharide.
Am. J. Respir. Cell Mol. Biol.
22:
604-612
32. Gereda, J. E., D. Y. Leung, A. Thatayatikom, J. E. Streib, M. R. Price, M. D. Klinnert, and A. H. Liu. 2000. Relation between house-dust endotoxin exposure, type 1 T-cell development, and allergen sensitisation in infants at high risk of asthma. Lancet 355: 1680-1683 [Medline].
33.
Schwartz, D. A..
2001.
Does inhalation of endotoxin cause asthma?
Am. J. Respir. Crit. Care Med.
163:
305-306
This article has been cited by other articles:
 |
|
 |
|
  A. E. John, M. S. Thomas, A. A. Berlin, and N. W. Lukacs Temporal Production of CCL28 Corresponds to Eosinophil Accumulation and Airway Hyperreactivity in Allergic Airway Inflammation Am. J. Pathol., February 1, 2005; 166(2): 345 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Roviezzo, F. Del Galdo, G. Abbate, M. Bucci, B. D'Agostino, E. Antunes, G. De Dominicis, L. Parente, F. Rossi, G. Cirino, et al. Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate PNAS, July 27, 2004; 101(30): 11170 - 11175. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Zhang, M. P. Soares, Y. Guan, S. Matheravidathu, R. Wnek, K. E. Johnson, A. Meisher, S. A. Iliff, J. S. Mudgett, M. S. Springer, et al. Functional Expression and Characterization of Macaque C-C Chemokine Receptor 3 (CCR3) and Generation of Potent Antagonistic Anti-macaque CCR3 Monoclonal Antibodies J. Biol. Chem., September 6, 2002; 277(37): 33799 - 33810. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Proc. Am. Thorac. Soc. | Am. J. Respir. Crit. Care Med. |