ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Relationship between interleukin-13 and transferrin receptor-1 responses in the pathogenesis of asthma  (#243)

Amber Pillar 1 , Alexandra Brown 1 , Jemma Mayall 1 , Jessica Weaver 1 , Ama-Tawiah Essilfie 2 , Gabriela Hoefel 1 , Md Khadem Ali 3 , Richard Kim 4 , Chantal Donovan 4 , Henry Gomez 1 , Kanth Swaroop Vanka 1 , Hock Tay 1 , Nazanin Kermani 5 , Yi-ke Guo 5 , Sharon Mumby 6 , Ian Adcock 6 , Greg Anderson 7 , David Fraser 2 , Daniel Johnstone 8 , Elizabeth Milward 9 , Philip Hansbro 4 , Peter Wark 1 10 , David Reid 2 , Paul Foster 1 , Jay Horvat 1
  1. The University of Newcastle and Hunter Medical Research Institute , Newcastle, NSW, Australia
  2. QIMR-Berghofer Institute of Medical Research , Brisbane, QLD, Australia
  3. Division of Pulmonary and Critical Care Medicine , Stanford University , Stanford, California , USA
  4. Center for Inflammation , Centenary Institute and University of Technology, Sydney , NSW, Australia
  5. Department of Computing & Data Science Institute, Imperial College London, London, UK
  6. Airways Disease, National Heart & Lung Institute, Imperial College London, London, UK
  7. Faculty of Science, Thompson Rivers University, Kamloops, British Columbia, Canada
  8. Discipline of Physiology, Bosch Institute, University of Sydney, Sydney, NSW, Australia
  9. The University of Newcastle , Newcastle, NSW, Australia
  10. Department of Respiratory and Sleep Medicine, John Hunter Hospital , Newcastle, NSW, Australia

Clinical and experimental evidence highlights an important role for altered iron metabolism in pathogenesis and severity of lung diseases, including asthma, idiopathic pulmonary fibrosis(IPF), chronic obstructive pulmonary disease(COPD) and cystic fibrosis(CF). Our previous studies in clinical and experimental asthma, show elevated iron in airway cells and tissues, which correlates with worsened lung function and development of key disease features. We have shown increased levels of the iron uptake protein, transferrin receptor (TFR)1, in airways, whilst associating increased TFR1 responses with increased type 2(T2) cytokine responses and decreased lung function. This study examined the relationship between the T2 cytokine, interleukin (IL)-13, and TFR1 responses, and the role of increased TFR1, in asthma pathogenesis.

We show that TFR1 is predominantly increased on macrophages and epithelial cells in experimental asthma, and that airway macrophage numbers in asthma patients positively correlate with TFR1 expression. Intranasal anti-TFR1 monocloncal antibody(αTFR1) administration significantly reduces the numbers of TFR1hi macrophages, but not TFR1hi epithelial cells, in HDM-induced disease. Importantly, αTFR1 administration reduces airflow obstruction and inflammation, reduces mucus secreting cell(MSC) numbers & fibrosis in the airway wall in HDM-induced experimental asthma. Interestingly, αTFR1 has no effect on HDM-induced IL-13, but significantly suppresses matrix metalloprotease(MMP)9, which is highly implicated in airway remodelling, expression in the lungs. Recombinant mouse (rm)IL-13 increases TFR1 expression in murine bone marrow-derived macrophages(BMDMs) & intranasal administration of anti-IL-13 monoclonal antibody(αIL-13) reduces the numbers of TFR1hi macrophages in HDM-induced asthma. Significantly, rmIL-13 and HDM stimulation of BMDMs increases MMP9 expression.

Our studies highlight an important role for IL-13-mediated alterations in iron metabolism in asthma pathogenesis. These data may highlight potential for therapeutic manipulation of TFR1 and/or iron metabolism for the treatment of asthma and other respiratory diseases associated with altered iron metabolism in airways including IPF, CF and COPD.