The metalloprotease-disintegrin ADAM8 is essential for the development of experimental asthma.
BACKGROUND
Expression of the metalloprotease ADAM8 is increased in patients with asthma, but the functional significance of elevated ADAM8 expression in the context of asthma pathogenesis remains elusive.


OBJECTIVE
To study development of asthma in ADAM8-deficient mice.


METHODS
Ovalbumin-induced asthma was studied in wild-type, ADAM8-deficient, and ADAM8-chimeric mice. Lung inflammation was assessed by histology, analysis of bronchoalveolar lavage, and airway hyperresponsiveness.


RESULTS
ADAM8-deficient mice are highly resistant to the development of ovalbumin-induced airway inflammation and hyperresponsiveness. ADAM8 expression was induced in both hematopoietic cells and the nonhematopoietic microenvironment after induction of asthma, and ADAM8 expression in both cell populations was required for the full manifestation of asthma. Interestingly, loss of ADAM8 on T cells alone was sufficient to significantly decrease the asthma response. The attenuated response was not due to an intrinsic defect in antigen presentation or cytokine production but reflected an impaired migration of T cells, eosinophils, CD11b(+) CD11c(-), and CD11c(+) cells from blood vessels to the lung and alveolar space, suggesting a general hematopoietic cell deficiency in the absence of ADAM8.


CONCLUSIONS
The results show that ADAM8 plays a proinflammatory role in airway inflammation. The milder disease outcome in the absence of ADAM8 suggests that this protein might be an interesting new target in treatment of this, and potentially other, inflammatory diseases in which recruitment of inflammatory cells is an essential part of pathogenesis.
Naus
Silvia
S
Biomedical Research Centre, University of British Columbia, Vancouver, BC, Canada.
Blanchet
Marie-Renée
MR
Gossens
Klaus
K
Zaph
Colby
C
Bartsch
Jörg W
JW
McNagny
Kelly M
KM
Ziltener
Hermann J
HJ
D051722:ADAM Proteins / Q000276:immunology*; D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D001249:Asthma / Q000235:genetics* / Q000276:immunology*; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D007249:Inflammation / Q000276:immunology; D008565:Membrane Proteins / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D015703:Antigens, CD; D008565:Membrane Proteins; D010047:Ovalbumin; D051722:ADAM Proteins; C489402:Adam8 protein, mouse