EGFR stimulation enables IL-6 trans-signalling via iRhom2-dependent ADAM17 activation in mammary epithelial cells

• Published in: Biochimica et biophysica acta. Molecular cell research 2023-10, Vol.1870 (7), p.119489-119489, Article 119489
• Main Authors: Schumacher, Neele, Thomsen, Ilka, Brundert, Florian, Hejret, Vaclav, Düsterhöft, Stefan, Tichý, Boris, Schmidt-Arras, Dirk, Voss, Matthias, Rose-John, Stefan
• Format: Article
• Language: English
• Subjects: ADAM17; EGFR; IL-6 trans-signalling; Interleukin-6; iRhom2
• ISSN: 0167-4889; 1879-2596
• DOI: 10.1016/j.bbamcr.2023.119489

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFR-downstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer. •EGFR activation induces IL-6 expression and sIL-6R release.•Activity of ADAM17 is regulated by EGFR signalling and ERK phosphorylation.•iRhom2 is an EGFR target gene.•EGFR signalling stimulates inflammatory gene expression.