The Amphiregulin-Epidermal Growth Factor Receptor axis as a therapeutic target in Sepsis

Rebecca Walsh¹Timothy Arthur Chandos Snow¹Alexandra Zapata Martinez¹David Brealey^1,2Mervyn Singer¹Abhishek Das^2,3Nishkantha Arulkumaran^1*

• ¹University College London, London, United Kingdom
• ²NIHR University College London Hospitals Biomedical Research Centre, London, United Kingdom
• ³University College London Division of Infection and Immunity, London, United Kingdom

The Epidermal Growth Factor Receptor (EGFR) and its ligand, amphiregulin (AREG) are critical for epithelial cell proliferation but their important role in inflammation and infection is increasingly described. We recently discovered that the EGFR ligand, amphiregulin, could iden5fy a cohort of infants with sepsis, even when CRP was low, iden5fying it as a poten5ally adjunc5ve biomarker for early infec5on. Its role in adult sepsis however, has yet to be delineated.We conducted a prospective observational study of 42 critically ill septic adult patients on the Intensive Care Unit, comparing serum amphiregulin levels and the frequencies of EGFR-expressing myeloid and lymphoid cells (using spectral flow cytometry) in sepsis survivors and non-survivors, and 20 healthy volunteers. We demonstrate, for the first time, the strong association between serum amphiregulin and in-hospital mortality (AUROC=0.87). Moreover, we demonstrate that a higher frequency of circulating CD4 + and CD8 + lymphocytes express either the ligand (AREG) or receptor (EGFR) ex vivo, in sepsis, and expression of CD4 + lymphocyte EGFR was associated with several features of immunosuppression.Together, our data suggest that EGFR-signalling represents a novel candidate of T cell dysregulation in sepsis and warrants further investigation.