Airway macrophages in health and disease Tracy Hussell

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1 Prof. Airway Macrophages in Health and Disease Director, Manchester Collaborative Centre for Inflammation Research (MCCIR), Professor of Inflammatory Disease University of Manchester Manchester, M13 9PT 1 tracy.hussell@manchester.ac.uk A better understanding of macrophages in their tissue specific context Asthma COPD Idiopathic pulmonary fibrosis Cystic fibrosis Lung cancer Bronchitis Bronchiectasis Pneumonia Infection 2 In the absence of antigen macrophages are enhanced in number and activation in the absence of CD200 Epithelium Mo 600 [TNF] (pg/ml) CD200R Alveolar Macs (x10 4 ) MHC II GM CD200R * WT CD200-/ ** WT CD200-/- EC + AM EC + AM + IFN-γ 3 RJ Snelgrove, J Goulding... T Hussell, A critical function for CD200 in lung immune homeostasis and the severity of influenza infection, Nature Immunol.,

2 Commensal synchronisation dependent on host genetics Naïve Day 7 influenza Day 7 influenza 4 Naïve Lowering the threshold of lung innate immune cell activation alters susceptibility to secondary bacterial superinfection, Goulding J, GodleeA, VekariaS, HiltyM, Snelgrove R, HussellT. J Infect Dis., 2011 Oct 1; 204(7): Airway macrophages: never the same again Neutrophilic inflammation Eosinophilic inflammation T cell inflammation 5 Airway Lung Blood Co-infected 48 hrs post S. pneumoniae PBS HDM 6 Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung; Habibzay M, Saldana JI, Goulding J, Lloyd CM, HussellT., Mucosal Immunol Sep; 5(5):

3 Does an altered health exist in chronic (or following resolution of acute) lung diseases? A different way of interacting with the environment 7 Blindfolding airway macrophages CD200R TREM2 Axl 8 Weeks following RSV infection Co-stimulation: a requirement for adaptive immunity alone? 9 CurrOpinImmunol Feb; 21(1):38-46, TREM and TREM-like receptors in inflammation and disease, Ford JW, McVicar DW. 3

4 Sequestering signalling adapters: the IL-33 receptor ST2 10 The altered phenotype of airway macrophages RSV (or PBS) Sort alveolar macrophage 11 MicroRNAs: the fine-tuners of Toll-like receptor signalling, O'Neill, Sheedy & McCoy, Nature Reviews Immunology 11,

5 Long lived alterations caused by epigenetic changes Naive Resolved p 13 Generic mirna repertoire changes in disparate inflammatory diseases Generic mirna changes post inflammation 14 Generic mrna changes in inflammation resolution 15 5

6 mirnas high in naive Linking mirna and mrna 16 mirna: linking over-regulation and TLR desensitisation TNF expression Anti mir Changing naïve to resolved LPS Changing resolved to naive 17 Airway macrophages are long lived No infection RSV infection 18 PKH26 Red Fluorescent cell lipophilic linker 6

7 What causes these changes in airway macrophages? TAM receptors and the removal of apoptotic cells 19 Immunobiology of the TAM receptors, Nat Rev Immunol May; 8: 327, Lemke & Rothlin Influenza enhances Axl on alveolar macrophages BALB/c C57BL6 Isotype Day0 Day4 Day8 Day14 Day21 Day42 Isotype Day0 Day4 Day8 Day11 Day14 Day21 Day42 Axl expression

8 Hyaluronic acid (HA) HAS-1/2 increased 22 Jiang et al., 2011 PhysiolRev. 91, Inhibits complement-dependent phagocytosis Lauer et al.,2013 J Biol Chem., 288(1), With Tony Day & Viranga Tilakaratna Conclusions Production of ligands for negative regulators on airway macrophages Trem2 Has a target in TLR4 mrna Blocks TLR responses Inhibits TLR and cytokine receptor signalling 24 8

9 Team Hussell focus Immune regulation in the healthy lung Why spontaneous remission/reactivation? Why do some patients respond to treatment, but others not? What is the molecular basis for patient stratification All provide clues to disease pathogenesis Thanks to: Lab members: Toshifumi Fujimori Tom Bell Dr Samira Salek-Ardakani Maryam Habibzay Cheryl Lai Mark Fife Eleni Tsitsiou Dr Alexandra Godlee Dr John Goulding Dr Robert Sanders Dr Robert Snelgrove Dr Erika Wissinger Dr Ian Humphreys Professor Clare Lloyd MCCIR Dr Fiona Foster (Centre manager) Professor Ashley Woodcock Professor Ian Kimber Dr Stuart Farrow Professor Martin Humphries Professor Ian Jacobs Dr Rose Maciewicz (AZ) Professor Sara Rankin Dr Malcolm Skingle (GSK) Professor Tim Williams Mentors Professor Ita Askonas Professor Peter Openshaw Professor Mark Feldmann Funding: Higher Education Innovation Funding Medical Research Council National Institute for Health, BBSRC, European Union, WellcomeTrust 27 9