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

Abstract

A disintegrin and a metalloproteinase domain 9 (ADAM9**) is known to be expressed by monocytes and macrophages. Herein, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein is stored in the gelatinase and specific granules and the secretory vesicles of human PMNs. Unstimulated PMNs express minimal quantities of surface ADAM9, but activation of PMNs with degranulating agonists rapidly (within 15 min) increases PMN surface ADAM9 levels. Human PMNs produce small quantities of soluble forms of ADAM9 (sADAM9). Surprisingly, ADAM9 degrades several extracellular matrix (ECM) proteins including fibronectin, entactin, laminin, and insoluble elastin as potently as MMP-9. However, ADAM9 does not degrade types I, III, or IV collagen, or denatured collagens in vitro. To determine whether Adam9 regulates PMN recruitment or ECM protein turnover during inflammatory responses, we compared wild type (WT) and Adam9−/− mice in bacterial lipopolysaccharide (LPS)- and bleomycin-mediated acute lung injury (ALI). Adam9 lung levels increase 10-fold during LPS-mediated ALI in WT mice (due to increases in leukocyte-derived Adam9), but Adam9 does not regulate lung PMN (or macrophage) counts during ALI. Adam9 increases mortality, promotes lung injury, reduces lung compliance, and increases degradation of lung elastin during LPS- and/or bleomycin-mediated ALI. Adam9 does not regulate collagen accumulation in the bleomycin-treated lung. Thus, ADAM9 is expressed in an inducible fashion on PMN surfaces where it degrades some ECM proteins, and promotes alveolar-capillary barrier injury during ALI in mice.

ADAM9 silencing inhibits breast tumor cells transmigration through blood and lymphatic endothelial cells

“…In particular for ADAM9, it was demonstrated that it is able to cleave laminin and promote tumor cell invasion [27]. ADAM9 also efficiently degraded several other extracellular matrix (ECM) proteins besides laminin, including fibronectin, entactin and insoluble elastin, in a model of acute lung injury [28]. In our experimental model, silencing of ADAM9 significantly decreased ADAM15 expression, and it is known that one of the variants of ADAM15 is related to greater catalytic activity, resulting in more aggressive breast tumors [29].…”

Bioactive extracellular matrix fragments in lung health and disease

“…These glycoproteins transduce both biochemical and mechanical signals between ECM and cells to influence cell survival, differentiation, and migration (89). Laminins are degraded by serine protease and metalloprotease family members (90,91). Laminin 332 (also known as laminin 5) is a component of multiple basement membranes and is implicated in hemidesmosome formation (92).…”

ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

“…ADAM9 knockout mice (129Sv ϫ CD57BL/6) do not show an obvious phenotype other than reduced neovascularization in the cornea pocket assay (204). In the lung, ADAM9 deficiency (C57BL/6) conferred protection against LPS-or bleomycin-induced lung inflammation (159). This protection was explained by the ability of ADAM9 to degrade lung elastin fibers leading to reduced lung compliance and disruption of the alveolar-capillary barrier.…”

“…ADAM9 is expressed at a low level in the lung and is upregulated in experimentally induced acute lung inflammation, a finding that was explained by an increase in leukocyte-derived ADAM9 (159). In vitro, the protease was found on monocytic cells, neutrophils, epithelial cells, and vascular SMCs.…”

“…In vitro, the protease was found on monocytic cells, neutrophils, epithelial cells, and vascular SMCs. In neutrophils, the protease is stored in granules and upregulated on the surface upon degranulation (159). Only a few substrates were described including the insulin B chain, insulin-like growth factor-binding proteins, amyloid precursor protein, some ErbB ligands, angiotensin-converting enzyme 1, ADAM10, and ECM proteins (38,122,137,157).…”