This Article Full Text Full Text (PDF) Online Supplement All Versions of this Article: 200606-839OCv1 175/3/243    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Whitehead, G. S. Articles by Cook, D. N. Search for Related Content PubMed PubMed Citation Articles by Whitehead, G. S. Articles by Cook, D. N.

The Chemokine Receptor D6 Has Opposing Effects on Allergic Inflammation and Airway Reactivity

National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina; Immunobiology Center, Mt. Sinai School of Medicine, New York, New York; Division of Immunology, Infection, and Inflammation, University of Glasgow, Glasgow, United Kingdom

Correspondence and requests for reprints should be addressed to Donald N. Cook, Ph.D., Laboratory of Respiratory Biology, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Bldg. 101, Room E244, Research Triangle Park, NC 27709. E-mail: cookd{at}niehs.nih.gov

Rationale: The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)–associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown.

Objectives: This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease.

Methods: D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity.

Results: The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity.

Conclusions: The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma.

Key Words: chemokines • lung • D6 • allergic • transforming growth factor– •

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2–associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its function is unknown. What This Study Adds to the Field The absence of D6 increases airway inflammation, but reduces airway reactivity. Inhibiting D6 might attenuate airway responses in individuals with asthma.

 

This article has been cited by other articles:

				R. H. Wilson, G. S. Whitehead, H. Nakano, M. E. Free, J. K. Kolls, and D. N. Cook Allergic Sensitization through the Airway Primes Th17-dependent Neutrophilia and Airway Hyperresponsiveness Am. J. Respir. Crit. Care Med., October 15, 2009; 180(8): 720 - 730. [Abstract] [Full Text] [PDF]

				A. K. Bauer and E. A. Rondini REVIEW PAPER: The Role of Inflammation in Mouse Pulmonary Neoplasia Vet. Pathol., May 1, 2009; 46(3): 369 - 390. [Abstract] [Full Text] [PDF]

				Y. Bordon, C. A. H. Hansell, D. P. Sester, M. Clarke, A. McI. Mowat, and R. J. B. Nibbs The Atypical Chemokine Receptor D6 Contributes to the Development of Experimental Colitis J. Immunol., April 15, 2009; 182(8): 5032 - 5040. [Abstract] [Full Text] [PDF]

				C. S. McKimmie, A. R. Fraser, C. Hansell, L. Gutierrez, S. Philipsen, L. Connell, A. Rot, M. Kurowska-Stolarska, P. Carreno, M. Pruenster, et al. Hemopoietic Cell Expression of the Chemokine Decoy Receptor D6 Is Dynamic and Regulated by GATA1 J. Immunol., September 1, 2008; 181(5): 3353 - 3363. [Abstract] [Full Text] [PDF]

				F.-Y. Wu, Z.-L. Ou, L.-Y. Feng, J.-M. Luo, L.-P. Wang, Z.-Z. Shen, and Z.-M. Shao Chemokine Decoy Receptor D6 Plays a Negative Role in Human Breast Cancer Mol. Cancer Res., August 1, 2008; 6(8): 1276 - 1288. [Abstract] [Full Text] [PDF]

				W. C. Moore Update in Asthma 2007 Am. J. Respir. Crit. Care Med., May 15, 2008; 177(10): 1068 - 1073. [Full Text] [PDF]

				G. Trujillo, E. C. O'Connor, S. L. Kunkel, and C. M. Hogaboam A Novel Mechanism for CCR4 in the Regulation of Macrophage Activation in Bleomycin-Induced Pulmonary Fibrosis Am. J. Pathol., May 1, 2008; 172(5): 1209 - 1221. [Abstract] [Full Text] [PDF]

				C. V. McCulloch, V. Morrow, S. Milasta, I. Comerford, G. Milligan, G. J. Graham, N. W. Isaacs, and R. J. B. Nibbs Multiple Roles for the C-terminal Tail of the Chemokine Scavenger D6 J. Biol. Chem., March 21, 2008; 283(12): 7972 - 7982. [Abstract] [Full Text] [PDF]

				D. N. Cook and K. Bottomly Innate Immune Control of Pulmonary Dendritic Cell Trafficking Proceedings of the ATS, July 1, 2007; 4(3): 234 - 239. [Abstract] [Full Text] [PDF]

				C. Hansell and R. Nibbs Professional and Part-Time Chemokine Decoys in the Resolution of Inflammation Sci. Signal., May 1, 2007; 2007(384): pe18 - pe18. [Abstract] [Full Text] [PDF]