Tracy Hussell 2019

Prof Tracy Hussell

University of Manchester, UK

Keynote Speech: Innate sensing of lung health and disease

Abstract

Epithelial cell proliferation, division and differentiation are critical for lung barrier repair following inflammation, but the initial trigger for this process is unknown. Basal cells reside at variable frequency throughout the airway epithelium, immediately above the basement membrane and are responsible for normal epithelial barrier maintenance through transdifferentiation and replenishment. Basal cells in the adult trachea are dormant in health but re-enter cell cycle to repopulate damaged cells. However, the trigger for cell cycle re-entry and the decision for proliferation versus differentiation are unclear. We reasoned that a significant component of the damaged lung environment is the presence of apoptotic cells and that these might be the initiating factor for basal cell proliferation and their hyperplasia in lung disease. We show that basal cells express the TAM receptor Axl. The TAM (Tyro3, Mer and Axl) receptor tyrosine kinase family recognize apoptotic cells by binding the C-terminal sex hormone-binding globulin-like domain of Protein S or growth arrest specific-6 (Gas6), whose N-terminal Gla domains bridge the TAM receptors to phosphatidylserine on the surface of apoptotic cells. Here we define that sensing of apoptotic cells by Axl is a critical indicator for tracheal basal cell expansion, cell cycle re-entry and symmetrical cell division. Furthermore, once the pool of tracheal basal cells has expanded, silencing of Axl is required for their differentiation. Genetic depletion of Axl triggers asymmetrical cell division leading to epithelial cell differentiation and ciliated cell regeneration. This discovery has implications for conditions associated with epithelial barrier dysfunction, basal cell hyperplasia and continued turnover of dying cells in patients with chronic inflammatory pulmonary diseases.

Biography

Professor Tracy Hussell relocated to the University of Manchester in 2012 from Imperial College London to form the Manchester Collaborative Centre for Inflammation Research (MCCIR) underpinned by significant financial input from leading UK pharmaceutical companies. This centre has now evolved into the Lydia Becker Institute of Immunology and Inflammation. Developed and directed by Professor Hussell this new Institute houses in excess of 105  academic scientists working on explorative immunology in health and disease. In 2016 Professor Hussell was selected additionally to lead the Domain of Infection, Immunity, Inflammation and Repair that drives the research agenda in these areas across the whole University and its allied NHS Trusts.  Her research examines how innate immune health is retained in the respiratory tract, its modulation by inflammation and long term consequences of persistent alterations, including susceptibility to infection and the development of primary and metastatic lung cancers.  The research group interacts with clinicians and cardiothoracic surgeons in respiratory medicine at Wythenshawe Hospital South Manchester, paediatricians at the Manchester Royal Infirmary and clinical academics at the Christie Hospital. Professor Hussell is currently funded by a Wellcome Trust Investigator award, an MRC strategic award and investment in discovery science from GSK.  In April 2017 she was elected a Fellow of the Academy of Medical Sciences.