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Review
. 2009 May;13(5):523-40.
doi: 10.1517/14728220902889788.

ADAM8: a new therapeutic target for asthma

Martin D Knolle  1 , Caroline A Owen
Affiliations
Review

ADAM8: a new therapeutic target for asthma

Martin D Knolle et al. Expert Opin Ther Targets. 2009 May.

Abstract

Background: A proteinase with a disintegrin and a metalloproteinase domain-8 (ADAM8) has been linked to asthma.

Objective: To explore whether ADAM8 is a therapeutic target for asthma.

Methods: We reviewed literature on ADAM8's function and expression and activities in lungs of humans and mice with allergic airway inflammation (AAI). We used these data to generate hypotheses about the contributions of ADAM8 to asthma pathogenesis.

Conclusions: ADAM8 levels are increased in airway epithelium and airway inflammatory cells in mice with AAI and human asthma patients. Data from murine models of AAI indicate that ADAM8 dampens airway inflammation. It is not clear whether ADAM8 contributes directly to structural remodeling in asthmatic airways. Additional studies are required to validate ADAM8 as a therapeutic target for asthma.

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Figures

Figure 1
Figure 1. The domain structure of ADAM8 and known or potential functions of each domain
Structure & Potential Function of ADAM8 Most is known about the metalloproteinase (MP) and disintegrin domains of ADAM8. ADAM8 is an active MP and may cleave several cell proteins including adhesion molecules, cytokines, cytokine receptors, growth factors and leukocyte immunoglobulin receptors from cell surfaces. The disintegrin domain of ADAM8 binds to α9β1 integrin on osteoclasts but it is not clear whether it binds to other integrins expressed by leukocytes to regulate leukocyte adhesion or migration. The cytoplasmic tail of ADAM8 has SH3 binding domains but its role in binding to SH3-domain-containing intracellular proteins to regulate intracellular signaling has not been examined. ECM: extracellular matrix.
Figure 2
Figure 2. Schematic representation of the potential mechanism(s) by which ADAM8 may limit allergic airway inflammation (AAI)
Potential Mechanisms by which ADAM8 Reduces Allergic Airway Inflammation In A (top panel), L-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) on polymorphonuclear neutrophil (PMNs) and monocytes bind to their ligands (CD62P and CD34, respectively) on endothelial cells to promote PMN and monocyte rolling on endothelial cells which is the initial step in the transendothelial migration of these leukocytes. ADAM8 expressed on the surface of activated leukocytes in the vasculature of asthmatic subjects may shed L-selectin and possibly PSGL-1 from leukocyte surfaces to reduce the egress of PMNs and monocytes from the vasculature into the airways. In A (bottom panel), activated eosinophils express α4 integrin which binds to vascualar cell adhesion molecule-1 (VCAM-1) expressed on activated endothelial cells leading to the formation of podosome-like adhesive structures in which ADAM8 is localized on the surface of eosinophils. Eosinophil-derived ADAM8 may shed VCAM-1 from endothelial surfaces to reduce α4 integrin-VCAM-1-mediated eosinophil-endothelial-cell adhesion which may limit the migration of eosinophils into asthmatic airways. In B (top panel), ADAM8 expressed on activated leukocytes or bronchial epithelial cells in asthmatic subjects may cleave IL-1 RII and TNFR1 from leukocyte or epithelial surfaces which may decrease the pro-inflammatory signaling of IL-1β or TNF-α through their receptors in asthmatic airways. In B (bottom panel), ADAM8 may shed CD16 from the surfaces of various leukocytes. CD16 is a low-affinity IgG receptor and binding of IgG to this receptor promotes leukocyte activation, degranulation and survival. ADAM8 expressed on the surface of activated leukocytes in asthmatic airways may shed CD16 to reduce leukocyte activation and decrease leukocyte survival, which may reduce inflammation in asthmatic airways.
Figure 3
Figure 3. Schematic representation of the potential mechanisms by which ADAM8 may regulate airway remodeling in asthma
Potential Activities of ADAM8 in Remodeling of Asthmatic Airways We currently have no data linking ADAM8 to airway remodeling in asthma. Based upon its anti-inflammatory activities in murine models of allergic airway inflammation (AAI), we speculate that ADAM8 may indirectly reduce mucin gene expression and goblet cell metaplasia by decreasing the airway burden of inflammatory cells and their mucin-inducing proteinases. The growth factor-activating activities of ADAM8 have not yet been tested. However, if the metalloproteinase domain of ADAM8 that is expressed on the surface of activated leukocytes or bronchial epithelial cells in asthmatic airways plays a significant role in activating TGF-β family members, IGFs, or ligands for the EGFR, this would promote fibroblast activation and deposition of extracellular matrix (ECM) proteins to increase subepithelial fibrosis and fibroblast secretion of mitogens that induce airway smooth muscle cells (ASMC) proliferation. If ADAM8 that is expressed by activated bronchial epithelial cells sheds EGFR ligands from epithelial cell surfaces, this may also promote mucin secretion and goblet cell metaplasia in the airway epithelium of subjects with asthma. Alternatively, ADAM8 that is expressed by activated airway leukocytes or activated bronchial epithelial cells in asthmatic airways may reduce subepithelial fibrosis by degrading ECM proteins deposited by airway myofibroblasts.
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