ADAM17 and EGFR regulate IL-6 receptor and amphiregulin mRNA expression and release in cigarette smoke-exposed primary bronchial epithelial cells from patients with chronic obstructive pulmonary disease (COPD)

Abstract

Aberrant activity of a disintegrin and metalloprotease 17 (ADAM17), also known as TACE, and epidermal growth factor receptor (EGFR) has been suggested to contribute to chronic obstructive pulmonary disease (COPD) development and progression. The aim of this study was to investigate the role of these proteins in activation of primary bronchial epithelial cells differentiated at the air–liquid interface (ALI‐PBEC) by whole cigarette smoke (CS), comparing cells from COPD patients with non‐COPD. CS exposure of ALI‐PBEC enhanced ADAM17‐mediated shedding of the IL‐6 receptor (IL6R) and the EGFR agonist amphiregulin (AREG) toward the basolateral compartment, which was more pronounced in cells from COPD patients than in non‐COPD controls. CS transiently increased IL6R and AREG mRNA in ALI‐PBEC to a similar extent in cultures from both groups, suggesting that posttranslational events determine differential shedding between COPD and non‐COPD cultures. We show for the first time by in situ proximity ligation (PLA) that CS strongly enhances interactions of phosphorylated ADAM17 with AREG and IL‐6R in an intracellular compartment, suggesting that CS‐induced intracellular trafficking events precede shedding to the extracellular compartment. Both EGFR and ADAM17 activity contribute to CS‐induced IL‐6R and AREG protein shedding and to mRNA expression, as demonstrated using selective inhibitors (AG1478 and TMI‐2). Our data are consistent with an autocrine‐positive feedback mechanism in which CS triggers shedding of EGFR agonists evoking EGFR activation, in ADAM17‐dependent manner, and subsequently transduce paracrine signaling toward myeloid cells and connective tissue. Reducing ADAM17 and EGFR activity could therefore be a therapeutic approach for the tissue remodeling and inflammation observed in COPD.

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

“…These are short-term and transient effects in normal cells, which do not explain the progressive inflammatory lung disease of COPD patients that stopped smoking. However, several reports show that the abnormal characteristics of COPD epithelial cells, including reduced CFTR expression in situ, persist in culture [ 87 ], probably due to a combination of genetic factors and epigenetic imprinting. Furthermore, COPD patients, smokers, and former smokers show signs of persistent reduced CFTR function in upper and lower airways, which may contribute to chronic lung disease [ 80 ].…”

“…In differentiated primary bronchial epithelial cells (HBEC-ALI), inhibitors of EGFR and of ADAM17 completely abolished ADAM17 substrate shedding as well as EGFR-dependent CXCL8 mRNA induction [ 87 ], illustrating the strong interrelationship between the key elements of the EGFR/ADAM17 axis ( Figure 4 ).…”

“…The anti- and proinflammatory properties of the EGFR/ADAM17 signaling pathway are context and cell type dependent [ 18 ]. For instance, in airway epithelial cells, ADAM17 together with EGFR induces mRNA expression and protein release of CXCL8, a neutrophil chemotactic factor that promotes inflammation [ 7 , 87 , 105 ]. However, by shedding TNF receptor type 2 (TNFR2) [ 128 ], which antagonizes TNF- α , ADAM17 exhibits also anti-inflammatory properties [ 129 ].…”

“…Due to the involvement of EGFR/ADAM17 paracrine and autocrine signaling in several lung disorders [ 109 , 116 ], modulation of ADAM17 and EGFR activation in both COPD and CF is important, to keep the balance between anti-inflammatory processes and promotion of inflammation, and also between regeneration and excessive tissue remodeling. Indeed, we recently found that cigarette smoke induced shedding of the ADAM17 substrate amphiregulin (AREG), and IL-6R was enhanced in differentiated bronchial cells in culture obtained from COPD patients compared to non-COPD, suggesting that epigenetic factors controlling the activity of the ADAM17/EGFR axis are affected in COPD [ 87 ].…”

Novel biomarker genes which distinguish between smokers and chronic obstructive pulmonary disease patients with machine learning approach

“…AREG, an EGFR ligand generated by the ADAM17mediated shedding of pro-AREG proteins, stimulates the transcription of inflammatory mediators in bronchial epithelial cells [53]. Moreover, recent research illustrated that AREG-mediated IL-6 secretion is enhanced in differentiated bronchial cells from patients with COPD compared with the findings in cells from subjects without COPD [54,55]. CXCR4 is associated with the recruitment of lymphocytes to disease lesions [56].…”