ADAM-family metalloproteinases in lung inflammation: potential therapeutic targets

Abstract

-Acute and chronic lung inflammation is driven and controlled by several endogenous mediators that undergo proteolytic conversion from surface-expressed proteins to soluble variants by a disintegrin and metalloproteinase (ADAM)-family members. TNF and epidermal growth factor receptor ligands are just some of the many substrates by which these proteases regulate inflammatory or regenerative processes in the lung. ADAM10 and ADAM17 are the most prominent members of this protease family. They are constitutively expressed in most lung cells and, as recent research has shown, are the pivotal shedding enzymes mediating acute lung inflammation in a cell-specific manner. ADAM17 promotes endothelial and epithelial permeability, transendothelial leukocyte migration, and inflammatory mediator production by smooth muscle and epithelial cells. ADAM10 is critical for leukocyte migration and alveolar leukocyte recruitment. ADAM10 also promotes allergic asthma by driving B cell responses. Additionally, ADAM10 acts as a receptor for Staphylococcus aureus (S. aureus) ␣-toxin and is crucial for bacterial virulence. ADAM8, ADAM9, ADAM15, and ADAM33 are upregulated during acute or chronic lung inflammation, and recent functional or genetic analyses have linked them to disease development. Pharmacological inhibitors that allow us to locally or systemically target and differentiate ADAM-family members in the lung suppress acute and asthmatic inflammatory responses and S. aureus virulence. These promising results encourage further research to develop therapeutic strategies based on selected ADAMs. These studies need also to address the role of the ADAMs in repair and regeneration in the lung to identify further therapeutic opportunities and possible side effects. metalloproteinase; shedding; inflammation; edema; asthma ACUTE OR CHRONIC INFLAMMATION in the lung can lead to a fatal loss of lung functions. Acute inflammation resulting from infection, aspiration of gastric juice, or overventilation during intensive care is initially characterized by enhanced inflammatory mediator production, edema formation, and recruitment of innate immune cells with the risk of lung damage. Asthma, chronic obstructive pulmonary disease (COPD), and lung fibrosis are fatal chronic diseases that are driven by persistent inflammation with a lack of resolution and impaired tissue regeneration. Targeting the immune response is the underlying principle of many treatment strategies against these diseases (reviewed in Ref. 7).The cytokines, growth factors, receptors, and adhesion molecules that drive the inflammatory process are all under intensive scrutiny. Many of these molecules undergo functional modulation by limited proteolysis, bringing the participating proteases into the focus of attention. Among these proteases is a class of metalloproteinases that subdivides into the matrix metalloproteinases (MMP) and the families of a disintegrin and metalloproteinases (ADAM) and ADAM with trombospondin motif. MMPs have already been intensively investigated with resp...

Ectodomain shedding of CD99 within highly conserved regions is mediated by the metalloprotease meprin β and promotes transendothelial cell migration

“…The HCRs in CD99 are characterized by many aspartate residues, which are greatly preferred by meprin b (6), indicating possible coevolution of protease and substrate. As a consequence of these negatively charged motifs, CD99 is not cleaved by ADAM10/17, metalloproteases that prefer aliphatic amino acids (42) and have been shown to shed other adhesion molecules involved in TEM [e.g., JAM-A or L-selectin (1,43,44)]. This finding further demonstrates the specificity of meprin b for CD99.…”

“…Regulated intramembrane proteolysis (RIP) of cell adhesion molecules, such as junctional adhesion molecule (JAM)-A, intercellular adhesion molecule (ICAM)-1, and L-selectin, was shown to be essential for transendothelial migration (TEM) of inflammatory or cancer cells (1). Meprin b, a multidomain type I transmembrane metalloprotease, is an initiator of RIP, and structural studies revealed dimeric formation of the protease with the active site in proximity to the cell surface (2)(3)(4).…”

The ADAMs family of proteases as targets for the treatment of cancer

“…27 Following birth, experiments with conditional knockout mice suggest a critical role for ADAM17 in regulating immunity, inflammation and bone formation. [30][31][32] In contrast to the situation in mice, ADAM17 may not be required for development in humans. Recently, 2 families with a genetic deficiency of ADAM17 were identified.…”

Staphylococcus aureusα-toxin-mediated cation entry depolarizes membrane potential and activates p38 MAP kinase in airway epithelial cells

“…Hla treatment of airway epithelial cells results in activation of ADAM10 (60), which may affect several subsequent signaling modules by as yet unknown links in the transduction pathways including proinflammatory pathways (13). However, ADAM10 activation depends on the presence of extracellular calcium (25) and on calcium influx into the cytosol (23 (4,19,43), but the modes of activation are still elusive.…”