The Epidermal Growth Factor Receptor Regulates Cell Autonomous Pro-inflammatory Signalling in Keratinocytes

Student thesis: Doctoral ThesisDoctor of Philosophy


The Epidermal Growth Factor Receptor (EGFR) is a fundamental regulator of epidermal integrity. We recently reported the first loss of function mutation in EGFR in a patient with skin fragility and inflammation. Similar inflammatory phenotypes have been reported in cancer patients following treatment with EGFR inhibitors, sometimes with severe consequences. This inflammation has been suggested to be due to defects in barrier integrity induced by EGFR deficiency, facilitating microbial challenge that promotes inflammatory responses. Here we provide evidence that loss of EGFR function in basal keratinocytes in culture is sufficient to induce a profound pro-inflammatory phenotype characterised by increased bioactive chemokine release that promotes leukocyte migration. We further show this depends on EGFR-dependent control of a balance of active STAT3 and SHP2 that control pro-inflammatory cytokine production at the transcriptional level. Moreover, our data demonstrates that that these changes are not attributable to loss of cell-cell interactions within keratinocyte monolayers. We therefore conclude that EGFR functions under homeostatic conditions to maintain a gene expression programme that limits the expression of pro-inflammatory genes and their products. These roles of EGFR are in addition to its regulation of epithelial cell proliferation and differentiation, and may be important for maintaining the a normal, proliferative epidermis. This has implications for the clinical use of EGFR inhibitors, and suggests with the combined use of anti-inflammatory, e.g. STAT3 inhibitors, but not necessarily anti-microbial inhibitors, may benefit patients exhibiting pro-inflammatory responses. Our data also provides evidence that primary epithelial defects may be the causal drivers of inflammatory skin disease.
Date of Award1 Apr 2020
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMadeline Parsons (Supervisor) & John McGrath (Supervisor)

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