title: Adam8 limits the development of allergic airway inflammation in mice.
abstract: To determine whether a disintegrin and metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyperresponsiveness (AHR), we compared AAI and AHR in wild-type (WT) versus Adam8(-/-) mice in different genetic backgrounds sensitized and challenged with OVA or house dust mite protein extract. OVA- and house dust mite-treated Adam8(-/-) mice had higher lung leukocyte counts, more airway mucus metaplasia, greater lung levels of some Th2 cytokines, and higher methacholine-induced increases in central airway resistance than allergen-treated WT mice. Studies of OVA-treated Adam8 bone marrow chimeric mice confirmed that leukocyte-derived Adam8 predominantly mediated Adam8's anti-inflammatory activities in murine airways. Airway eosinophils and macrophages both expressed Adam8 in WT mice with AAI. Adam8 limited AAI and AHR in mice by reducing leukocyte survival because: 1) Adam8(-/-) mice with AAI had fewer apoptotic eosinophils and macrophages in their airways than WT mice with AAI; and 2) Adam8(-/-) macrophages and eosinophils had reduced rates of apoptosis compared with WT leukocytes when the intrinsic (but not the extrinsic) apoptosis pathway was triggered in the cells in vitro. ADAM8 was robustly expressed by airway granulocytes in lung sections from human asthma patients, but, surprisingly, airway macrophages had less ADAM8 staining than airway eosinophils. Thus, ADAM8 has anti-inflammatory activities during AAI in mice by activating the intrinsic apoptosis pathway in myeloid leukocytes. Strategies that increase ADAM8 levels in myeloid leukocytes may have therapeutic efficacy in asthma.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Knolle
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Anja
authors.initials: A
authors.lastname: Hergrueter
authors.forename: Kushagra
authors.initials: K
authors.lastname: Gupta
authors.forename: Francesca
authors.initials: F
authors.lastname: Polverino
authors.forename: Vanessa J
authors.initials: VJ
authors.lastname: Craig
authors.forename: Susanne E
authors.initials: SE
authors.lastname: Fyfe
authors.forename: Muhammad
authors.initials: M
authors.lastname: Zahid
authors.forename: Perdita
authors.initials: P
authors.lastname: Permaul
authors.forename: Manuela
authors.initials: M
authors.lastname: Cernadas
authors.forename: Gilbert
authors.initials: G
authors.lastname: Montano
authors.forename: Yohannes
authors.initials: Y
authors.lastname: Tesfaigzi
authors.forename: Lynette
authors.initials: L
authors.lastname: Sholl
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
authors.forename: Elliot
authors.initials: E
authors.lastname: Israel
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Owen
mesh_terms: D051722:ADAM Proteins / Q000276:immunology* / Q000378:metabolism; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001249:Asthma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004804:Eosinophils / Q000276:immunology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D015703:Antigens, CD; D008565:Membrane Proteins; D051722:ADAM Proteins; C068490:ADAM8 protein, human; C489402:Adam8 protein, mouse