The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity.
BACKGROUND
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.


OBJECTIVE
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.
Whitehead
Gregory S
GS
National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Wang
Tie
T
DeGraff
Laura M
LM
Card
Jeffrey W
JW
Lira
Sergio A
SA
Graham
Gerard J
GJ
Cook
Donald N
DN
D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology*; D019742:Chemokines, CC / Q000032:analysis / Q000378:metabolism*; D004804:Eosinophils / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000737:chemistry / Q000276:immunology*; D008173:Lung Diseases, Obstructive / Q000235:genetics / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D016210:Methacholine Chloride / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D054447:Receptors, CCR10; D019707:Receptors, Chemokine / Q000235:genetics / Q000502:physiology*; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D000097628:Chemokine Receptor D6
D000485:Allergens; D019742:Chemokines, CC; D016210:Methacholine Chloride; D010047:Ovalbumin; D054447:Receptors, CCR10; D019707:Receptors, Chemokine; D053773:Transforming Growth Factor beta1; D000097628:Chemokine Receptor D6