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Review
. 2018 Jan 9:2018:1067134.
doi: 10.1155/2018/1067134. eCollection 2018.

The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Marta Stolarczyk  1 , Bob J Scholte  1   2
Affiliations
Review

The EGFR-ADAM17 Axis in Chronic Obstructive Pulmonary Disease and Cystic Fibrosis Lung Pathology

Marta Stolarczyk et al. Mediators Inflamm. .

Abstract

Chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF) share molecular mechanisms that cause the pathological symptoms they have in common. Here, we review evidence suggesting that hyperactivity of the EGFR/ADAM17 axis plays a role in the development of chronic lung disease in both CF and COPD. The ubiquitous transmembrane protease A disintegrin and metalloprotease 17 (ADAM17) forms a functional unit with the EGF receptor (EGFR), in a feedback loop interaction labeled the ADAM17/EGFR axis. In airway epithelial cells, ADAM17 sheds multiple soluble signaling proteins by proteolysis, including EGFR ligands such as amphiregulin (AREG), and proinflammatory mediators such as the interleukin 6 coreceptor (IL-6R). This activity can be enhanced by injury, toxins, and receptor-mediated external triggers. In addition to intracellular kinases, the extracellular glutathione-dependent redox potential controls ADAM17 shedding. Thus, the epithelial ADAM17/EGFR axis serves as a receptor of incoming luminal stress signals, relaying these to neighboring and underlying cells, which plays an important role in the resolution of lung injury and inflammation. We review evidence that congenital CFTR deficiency in CF and reduced CFTR activity in chronic COPD may cause enhanced ADAM17/EGFR signaling through a defect in glutathione secretion. In future studies, these complex interactions and the options for pharmaceutical interventions will be further investigated.

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Figures

Figure 1
Figure 1
Common features of CF and COPD. CF and COPD lung disease share many common clinical manifestations despite the differences with respect to etiology. Mutations in the CFTR gene determine CF lung disease. Recently, CS has been shown to affect CFTR channel activity and this is recognized as a factor that may contribute to a CF-like phenotype in COPD. Thus, COPD has been recently described as “acquired CF.”
Figure 2
Figure 2
ADAM17 domain structure. ADAM17 is an atypical member of the ADAM family. It has additional disulfide bonds in the metalloprotease domain, and it lacks two calcium binding sites in the disintegrin domain. The membrane proximal domain (MPD), replacing the cysteine-rich and EGF-like domains, with a novel alpha/beta fold has a shorter cysteine-rich segment. The MPD has cysteine residues determining the ADAM17 conformation (open/closed) and ADAM17 protease activity (active/inactive switch). The MPD is in close proximity to the active site likely due to a C-shaped conformation of the extracellular part of mature ADAM17 [99]. ADAM17 lacks an EGF-like domain, so the MPD is followed by the juxtamembrane region “conserved ADAM17 dynamic interaction sequence” (CANDIS) involved in substrate recognition [162]. The trans-membrane region ends with a cytoplasmic tail with phosphorylation sites, which are likely important for ADAM17 activity and trafficking [–101].
Figure 3
Figure 3
ADAM17 dependent paracrine and autocrine signaling. A disintegrin and metalloproteinase 17 (ADAM17), also known as a tumor necrosis factor-α converting enzyme (TACE), is involved in the immune defense mechanisms mediated by epithelial cells. ADAM17 releases extracellular domains of transmembrane proteins to produce soluble bioactive signaling proteins taking part in autocrine (activation of receptors within the same epithelial cell layer) and paracrine signaling (activation of cellular receptors on underlying neighboring cells, also termed transactivation). Among the ADAM17 substrates are (1) adhesion proteins (L-selectin, ICAM), (2) transmembrane mucins (MUC-1), (3) membrane-bound cytokines (TNF-α), (4) growth factors (AREG) and other ligands of EGFR (TGF-α, EREG, HB-EGF, and epigen), and (5) cytokine receptors (IL-6R, TNF-R). Ectodomain shedding provides the mechanism for autocrine and paracrine signaling. IL-6R shed from epithelial cells transactivates gp130 on the underlying myofibroblasts, whereas AREG shed from epithelial cells activates EGFR on epithelial cells or on the underlying fibroblasts. The ADAM17 inhibitor TIMP-3 inhibits the ADAM17 proteolytic activity.
Figure 4
Figure 4
The ADAM17/EGFR axis. The EGFR/ADAM17 positive feedback loop likely involves activation of ADAM17 via the EGFR/MAPK pathway and direct interaction of ERK1/2 with ADAM17. Additionally, by cleavage of Notch1 from a non-small lung carcinoma cell line ADAM17 regulates transcription of EGFR mRNA and increases EGFR expression on the cell surface, providing another mechanism contributing to positive feedback regulation.
Figure 5
Figure 5
ADAM17 is a redox-sensitive protein. The ADAM17 membrane proximal domain (MPD), which is in close proximity to the active site, is sensitive to extracellular (or intravesicular) redox changes. This redox-sensitive ADAM17 activity is regulated by thiol-disulfide isomerization mediated by protein disulphide isomerase (PDI), an oxidoreductase sensitive to redox changes. PDI changes the disulfide bridge pattern and thus the conformation of the extracellular protease domain from an open active to a closed inactive state, by direct interaction with the membrane proximal domain (MPD), leading to the inhibition of ADAM17 proteolytic activity. Redox sensitive conformational changes likely make ADAM17 sensitive to the extracellular redox potential, which is dependent on glutathione (GSH/GSSH) and ROS.
Figure 6
Figure 6
Classic and trans IL-6R signaling. In “classic” signaling membrane-bound IL-6R stimulated by secreted IL-6 associates with a homodimer of signal transducing glycoprotein (gp130) to activate downstream signaling molecules, including the ubiquitous transcription factor STAT-3. In trans-signaling, the soluble form of IL-6R (sIL-6R,) generated either by ADAM17 or by alternative mRNA splicing, binds to IL-6 and this IL-6/IL-6R complex activates gp130 on the airway epithelial cells (autocrine IL-6R trans-signaling) or underlying fibroblasts, myoblasts, or smooth muscle cells that do not express IL-6R (paracrine IL-6R trans-signaling), but do express gp130 to evoke activation of STAT-3 signaling.
Figure 7
Figure 7
ADAM17/EGFR signaling an important player in CF and COPD lung disease. In airway epithelial cells in culture, both CFTR deficiency [61] and cigarette smoke exposure [87] cause enhanced activity of the EGFR/ADAM17 signaling cascade, and thus enhanced release of proinflammatory cytokines and growth factors that are ADAM17 substrates and signaling molecules that are downstream of the EGFR/MAPK pathway (Figure 1) including the proinflammatory CXCL8 (IL-8). In chronic lung disease, this could contribute to mucous metaplasia, inflammation, and tissue remodeling. A potential link between CFTR deficiency, COPD, and EGFR/ADAM17 activity (dashed arrows) is the extracellular redox potential, which is in part dependent on CFTR-related glutathione transport [30, 165, 166], and which in turn regulates ADAM17 activity (Figure 5). In COPD, CS induced long-term downregulation of CFTR expression [16, 47, 80] can have the same long-term effect, in addition to the acute oxidative stress caused by cigarette smoke. In this figure, we focus on two canonical ADAM17 substrates: proinflammatory IL-6 receptor (IL-6R) and growth factor amphiregulin (AREG). AREG is proteolytically cleaved by ADAM17 from airway epithelial cells and activates EGFR in the airway epithelial cells and on the underlying fibroblasts. IL-6R trans-signaling requires ADAM17-mediated shedding of the extracellular domain or alternative mRNA splicing. The soluble sIL-6R binds to IL-6 creating IL-6/sIL-6R complexes that trans-activate gp130 on the underlying myofibroblasts and myeloid cells. Signals transduced by AREG and IL-6R shed from airway epithelial cells converge in combined activation of the transcription factor STAT3 in myofibroblasts and smooth muscle cells. STAT3 is involved in fibrotic responses and inflammatory lung disease, and a modifier of CF lung disease [221]. Based on available literature cited in text, enhanced EGFR/ADAM17 signaling may contribute to hyperinflammation and epithelial metaplasia, fibroblast and smooth muscle cell activation, angiogenesis, and net deposition of extracellular matrix (tissue remodeling) observed in COPD and CF lung disease.
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