Adam8 Limits the Development of Allergic Airway Inflammation in Mice

Abstract

To determine whether a disintegrin and a metalloproteinase-8 (Adam8) regulates allergic airway inflammation (AAI) and airway hyper-responsiveness (AHR), we compared AAI and AHR in wild type (WT) versus Adam8−/− mice in different genetic backgrounds sensitized and challenged with ovalbumin (OVA) or house dust mite protein extract (HDM). OVA- and HDM-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.

IL‐5‐stimulated eosinophils adherent to periostin undergo stereotypic morphological changes and ADAM8‐dependent migration

“…Further, copy number variation analyses of multiple populations placed ADAM8 in the top three of 61 implicated “asthma genes” . Studies with ADAM8‐deficient mice in models mimicking asthma have yielded conflicting results with ADAM8 implicated as either promoting or regulating eosinophil recruitment, airway responsiveness and remodelling . However, a recent article demonstrated that a peptide inhibitor of ADAM8 decreased airway eosinophil numbers, tissue remodelling and type 2 cytokines, and attenuated airway hyperresponsiveness in mice, supporting pro‐eosinophil recruitment and pro‐asthma roles for ADAM8.…”

Sputum ADAM8 expression is increased in severe asthma and COPD

“…Additionally, the mouse model used by Knolle et al. is unlikely to mimic the human airway as differences in ADAM8 expression on macrophages were reported between human cells and murine cells from their models. Therefore, further work is required to validate their findings in a human population.…”

ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils: Regulation of Expression and Contributions to Extracellular Matrix Protein Degradation during Acute Lung Injury

“…Equal numbers of cells from each genotype were incubated in triplicate at 37°C for 30 min with 1 mM PMSF to completely inactivate cell surface serine proteinases on PMNs which contribute to cleavage of the substrates studied (28,34,35,38,39). Samples were divided into two equal aliquots, and one aliquot was incubated for 30 min at 37°C with 1 mM 1,10 o-phenanthroline [a general inhibitor of MMPs and ADAM proteinases (28,40)], and the other aliquot was incubated without this inhibitor. PMNs or buffer alone were then incubated for 18 h at 37°C with 50 μg/ml DQ-FITC-conjugated type IV collagen (3 x 10 6 cells/assay), DQ-FITC-conjugated gelatin (3 x10 6 cells/assay), DQ-FITC-conjugated type I collagen (5 x10 6 cells/assay), or 20 mg/ml FITC-conjugated particulate elastin (Mesh 200–400; 5 x10 6 cells/assay) in Tris assay buffer (pH 7.4).…”