MCCIR AZ GSK Update Seminar Series
|Starts:||15:30 9 Nov 2015|
|Ends:||16:30 9 Nov 2015|
|What is it:||Seminar|
|Organiser:||Faculty of Life Sciences|
|Who is it for:||University staff, Adults, Current University students|
|Speaker:||Emma Connelly, Naoya Fujino|
The role of neurotrophic factors in airway immunity
Alveolar macrophages (M?s) are the first line of defence against inhaled pathogens and must be regulated to prevent unwanted inflammatory responses to innocuous antigens whilst still providing protection against pathogenic infections. The dominant cell-cell interactions in the healthy airways are between alveolar M?s and respiratory epithelial cells, which exert a range of immunomodulatory stimuli over M?s. These negative interactions between alveolar M?s and the airway epithelium, for example by CD200R and ?v?6-activated TGF?, are disrupted during inflammation due to down-regulation of epithelial surface receptors and/or epithelial damage. Often, during resolution of inflammation, these negative regulators are increased and contribute to subsequent bacterial complications. The lung is highly innervated and yet the influence of neurotrophic factors on airway macrophage function is unknown. The glial cell line derived neurotrophic family (GDNF) are distant members of the TGF-? superfamily and include the receptor GFR?2 and its ligand, neurturin (Nrtn). Though originally ascribed the function of nerve growth factors, we now show unique GFR?2 expression on airway macrophages, epithelial expression of neurturin and an up-regulation of GFR?2 on COPD airway macrophages. This novel observation implies neuroimmune modulatory circuits are evident in the lung and may be disrupted in chronic inflammatory conditions..
Axl receptor tyrosine kinase activates airway epithelial stem cells in response to injury
Repair and remodelling of the adult lung is postulated to rely on airway epithelial stem cell populations. These stem cell populations are dormant at steady state but can robustly activate in response to injury by proliferating and by differentiating into multiple descendants to replace damaged cells. Uncovering molecular pathways regulating the activation, proliferation and differentiation of airway epithelial stem cell populations is critical for better understanding of lung repair and remodelling processes.
To identify a signalling pathway regulating the airway stem cell function, we screened a kinase inhibitor library using human lung tissue-derived multi-potent cells at AstraZeneca. Through the screening and validation assays with siRNA-mediated knockdown approach, we found that Axl receptor tyrosine kinase negatively regulated epithelial differentiation of the human lung multi-potent cells in vitro. Histological assessments showed that Axl kinase was expressed by airway basal stem cells in human bronchioles and mouse trachea. We have currently found that Axl kinase stimulates cell cycle progression and promotes symmetric division of murine tracheal basal cells during H1N1/PR8 influenza A virus-induced injury. We have further observed that Axl negatively regulates ciliated cell differentiation of basal cells. Taken together, our collaborative and innovative approach of the compound screening using human tissue-derived cells and the in vivo validation study allowed us to identify the unexpected role of Axl kinase in the activation of airway epithelial stem cells.
Travel and Contact Information
Michael Smith Lecture Theatre
Michael Smith Building