Prof Tracy Hussell
Tracy Hussell – Research summary
Professor Tracy Hussell
Macrophage can assume an inflammatory, regulatory or wound healing phenotype depending on complex tissue-specific signals and local environmental cues. These diverse macrophage functions have mostly been examined during or immediately after an inflammatory event, whereas little is known about their plasticity in the steady state or how incoming inflammatory cells affect their phenotype and function once inflammation has resolved. These concepts are particularly relevant to the airway lumen that contains in health a resident mature alveolar macrophage population comprising 95% of all cells that can be washed out by bronchoalveolar lavage.
These macrophage occupy a unique niche, dominated by airway epithelium and exposed to innocuous environmental antigens and allergens that have avoided impaction in the upper nasopharynx. Such tolerance of inhaled environmental particles, that often contain proteolytic activity, mimics of TLR signalling complex molecules and lipid-binding activity and the ability to engage pattern recognition receptors, is mediated to a large extent by interaction of airway macrophage with regulatory proteins on the respiratory epithelium that set the inflammatory macrophage tone of the airspaces.
Inflammation in mucosal tissues does not occur in the presence of antigen alone, but requires a loss of structural integrity. In the lung we have identified a number of signals provided by epithelia and other structural components which dampen innate immunity in the absence of structural damage. These include CD200 that transmits a suppressive signal to airway macrophages via CD200R, TREM 2 that sequesters the Toll like receptor adapter MyD88 and TAM receptors that facilitate macrophage efferocytosis of apoptotic cells leading to macrophage de-sensitisation. Following chronic inflammation, these pathways are over-expressed and contribute to future exacerbation of disease by bacteria. All of these pathways are conserved in humans, but are yet to be investigated in defined patient cohorts with inflammatory lung disease. We will test the hypothesis that the remodelled epithelium over-regulates airway macrophages in patients with COPD or Asthma. Therapeutic manipulation of such regulatory pathways would re-set the inflammatory tone in the lung and prevent exacerbation of chronic disease.
Manchester Collaborative Centre for Inflammation Research (MCCIR)
Core Technology Facility,
The University of Manchester,
Telephone: 0161 2751537
Tracy Hussell completed her PhD at University College London where she identified Helicobacter pylori as an aetiological agent in human gut lymphomas. After her PhD Professor Hussell moved to Respiratory Medicine at St Mary's Hospital to study immunity and pathology to respiratory syncytial virus. In 1998 she accepted a lectureship in the Centre for Molecular Microbiology and Infection (CMMI) at Imperial College. She was subsequently awarded a career development fellowship by the Medical Research Council. Professor Hussell was awarded a Personal Chair in inflammatory disease at Imperial College London in 2006 and has developed a vibrant research group studying immune health and its deregulation in the lung. Professor Hussell is currently the Director of the Manchester Collaborative Centre for Inflammation Research (MCCIR) at The University of Manchester.
- Van Maele L, Fougeron D, Janot L, Didierlaurent A, Cayet D, Tabareau J, Rumbo M, Corvo-Chamaillard S, Boulenouar S, Jeffs S, Vande Walle L, Lamkanfi M, Lemoine Y, Erard F, Hot D, Hussell T, Ryffel B, Benecke AG, Sirard JC. Airway structural cells regulate TLR5-mediated mucosal adjuvant activity.Mucosal Immunol. 2013 Sep 25. doi: 10.1038/mi.2013.66.
- Findlay E.G., Danks L., Madden j., Cavanagh M.M., McNamee K., Snelgrove R.S., UCB Celltech, Feldmann M., Taylor P.C., Horwood N.J., Hussell T. A critical role for OX40L in the normal and inflamed joint. Accepted PNAS 2013.
- Hussell T and Bell T. Alveolar macrophages: plasticity in a tissue-specific context Nature Reviews in Immunology 2013
- Hussell T, Godlee A, Salek-Ardakani S, Snelgrove RJ. Respiratory viral infections: knowledge based therapeutics. Curr Opin Immunol. 2012 Aug;24(4):438-43.
- Edwards MR, Bartlett NW, Hussell T, Openshaw P, Johnston SL. The microbiology of asthma. Nat Rev Microbiol. 2012 Jun 6;10(7):459-71.
- Habibzay M, Saldana JI, Goulding J, Lloyd CM, Hussell T. Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung. Mucosal Immunol. 2012 Sep;5(5):524-34.
- Everitt AR, Clare S, Pertel T, John SP, Wash RS, Smith SE, Chin CR, Feeley EM, Sims JS, Adams DJ, Wise HM, Kane L, Goulding D, Digard P, Anttila V, Baillie JK, Walsh TS, Hume DA, Palotie A, Xue Y, Colonna V, Tyler-Smith C, Dunning J, Gordon SB; GenISIS Investigators; MOSAIC Investigators, Smyth RL, Openshaw PJ, Dougan G, Brass AL, Kellam P. IFITM3 restricts the morbidity and mortality associated with influenza. Nature. 2012;484(7395):519-23.
- Thomas Krausgruber, Katrina Blazek, Tim Smallie, Saba Alzabin, Helen Lockstone, Natasha Sahgal, Tracy Hussell, Marc Feldmann and Irina A Udalova IRF5 promotes inflammatory macrophage polarization and TH1-TH17 responses Nature Immunology 2011; 12 (3): 231 238.
- Hussell T, Goulding J. Structured regulation of inflammation during respiratory viral infection. Lancet Infect Dis. 10 (2010); 360-6
- Snelgrove, R.J.,Goulding, J., Didierlaurent,A.M., Lyonga,D., Vekaria, S., Edwards, L., Gwyer, E., Sedgwick, JD., Barclay, A.N., Hussell, T. A critical function for CD200 in lung immune homeostasis and the severity of influenza infection Nature Immunology 9 (2008):1074-83.
- Didierlaurent, A., Goulding, J., Snelgrove, R., Low, L., Bebien, M., Lawrence, T., van Rijt, L.S., Lambrecht, B.N., Sirard, J-C., Hussell, T. Sustained de-sensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection" J. Exp.Med 205 (2008):323-9.
- Fong, C.H.Y., Bebien, M., Didierlaurent , A., Nebauer, R., Hussell, T., Broide, D., Karin,M., Lawrence, T. An antiinflammatory role for IKK??through the inhibition of classical macrophage activation J. Exp. Med. 205 (2008):1269-1276.