The glial cell line-derived neurotrophic factor family in airway infectious disease

• Main Author: Connolly, Emma
• Other Authors: Hussell, Tracy ; Brough, David
• Published: University of Manchester 2018
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.740357

Alveolar macrophages reside in the healthy airspaces and are continuously exposed to environmental challenges. As such, mechanisms are in place to restrict their activity, including negative regulation by epithelial cells. Upon encountering a harmful pathogen, this inhibition is lost and pattern recognition receptors, such as toll-like receptors (TLRs), are activated. This stimulates the release of type I interferons, which exert anti-microbial actions on airway cells. The importance of neurotrophic factors in the immune response is becoming well established. However, research into their role in airway homeostasis and infectious disease is lacking. Therefore, in this thesis I aimed to determine which neurotrophic factors were highly expressed on airway macrophages and elucidate their potential role in homeostasis, as well as microbial clearance, of the airway. In this thesis, I have found that the glial cell line-derived neurotrophic factor (GDNF) family receptor, GFRα2, is highly expressed on mouse and human airway macrophages at steady state. However, the expression of the signalling partner for the GFRα receptors, the tyrosine kinase RET, is specifically induced in airway macrophages by type I interferons. Furthermore, TLR activation enhances the production and release of the GFRα2 ligand, neurturin, from airway epithelial cells. Therefore, I propose a novel role for the GDNF family in infectious disease, through modulation of airway macrophage anti-microbial activity.