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Role of A Disintegrin And Metalloprotease-12 in Neutrophil Recruitment Induced by Airway Epithelium

Cecilia Estrella^1,*, Natacha Rocks^2,*, Geneviève Paulissen², Florence Quesada-Calvo², Agnès Noël², Eva Vilain¹, Philippe Lassalle¹, Isabelle Tillie-Leblond^1,3, Didier Cataldo^2, and Philippe Gosset^1,

¹ INSERM U774, Biomolecules and Pulmonary Inflammation; Institut Pasteur; and Université de Lille II, Lille, France; ² Department of Biology of Tumours and Development, GIGA-Research (GIGA-I³), University of Liège and CHU of Liège, Liège, Belgium; and ³ Clinique des Maladies Respiratoires Hôpital Calmette, CHRU, Lille, France

Correspondence and requests for reprints should be addressed to Philippe Gosset, Ph.D., INSERM U774, Biomolecules and Pulmonary Inflammation, Institut Pasteur de Lille, 1 rue du Pr Calmette, BP245, 59019 Lille Cedex, France. E-mail: Philippe.Gosset{at}pasteur-lille.fr

Among proteases, metalloproteases are implicated in tissue remodeling, as shown in numerous diseases including allergy. ADAMs (A Disintegrin And Metalloprotease) metalloproteases are implicated in physiologic processes such as cytokine and growth factor shedding, cell migration, adhesion, or repulsion. Our aim was to measure ADAM-12 expression in airway epithelium and to define its role during the allergic response. To raise this question, we analyzed the ADAM-12 expression ex vivo after allergen exposure in patients with allergic rhinitis and in vitro in cultured primary human airway epithelial cells (AEC). Clones of BEAS-2B cells transfected with the full-length form of ADAM-12 were generated to study the consequences of ADAM-12 up-regulation on AEC function. After allergen challenge, a strong increase of ADAM-12 expression was observed in airway epithelium from patients with allergic rhinitis but not from control subjects. In contrast with the other HB-epidermal growth factor sheddases, ADAM-10 and -17, TNF- in vitro increased the expression of ADAM-12 by AEC, an effect amplified by IL-4 and IL-13. Up-regulation of ADAM-12 in AEC increased the expression of 3 and 4 integrins and to the modulation of cell migration on fibronectin but not on collagen. Moreover, overexpression of ADAM-12 in BEAS-2B enhanced the secretion of CXCL1 and CXCL8 and their capacity to recruit neutrophils. CD47 was strongly decreased by ADAM-12 overexpression, a process associated with a reduced adhesion of neutrophils. These effects were mainly dependent on epidermal growth factor receptor activation. In summary, ADAM-12 is produced during allergic reaction by AEC and might increase neutrophil recruitment within airway mucosa.

Key Words: ADAM-12 • allergy • airway epithelial cell • neutrophil • inflammation

CLINICAL RELEVANCE A Disintegrin And Metalloprotease (ADAM)-12 is a metalloprotease that possesses an important sheddase activity. ADAM-12 up-regulation during allergic airway diseases and its implication in the control of neutrophil recruitment by airway epithelial cells suggest its involvement in the control of airway inflammation.