Preventing exacerbation of chronic disease

Lung Immunity in Health and Disease

Tracy Hussell

Principal Investigator

Professor Tracy Hussell (Director)

Tel: 0161 275 1537

Email: tracy.hussell@manchester.ac.uk

See: University research profile | Lab members

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.

The regulation of airway macrophages by the respiratory epithelium in health

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.

persistence of hyaluronic acid (green) in the post-influenza infected lung adjaecent to airway macrophages expressing CD44 (red). Blue- DAPI

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.

Selected Publications

Fujimori T, Grabiec AM, Kaur M, Bell TJ, Fujino N, Cook PC, Svedberg FR, MacDonald AS, Maciewicz RA, Singh D, Hussell T. “The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung”. Mucosal Immunol. 2015 Sep;8(5):1021-30.

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. “OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis.”. Proc Natl Acad Sci U S A. 2014 Feb 11;111(6):2289-94

Hussell T, Bell TJ (2014). Alveolar macrophages: plasticity in a tissue-specific context. Nature Reviews Immunolology. 14(2):81-93

Sanders RD, Godlee A, Fujimori T, Goulding J, Xin G, Salek-Ardakani S, Snelgrove RJ, Ma D, Maze M, Hussell T (2013). Benzodiazepine augmented γ-amino-butyric acid signalling increases mortality from pneumonia in mice. Critical Care Medicine. 41(7):1627-36.

Habibzay M, Saldana JI, Goulding J, Lloyd CM, Hussell T.(2012) Altered regulation of Toll-like receptor responses impairs antibacterial immunity in the allergic lung. Mucosal Immunology. 5(5):524-34.

Snelgrove RJ, Jackson PL, Hardison MT, Noerager BD, Kinloch A, Gaggar A, Shastry S, Rowe SM, Shim YM, Hussell T, Blalock JE (2010). A critical role for LTA4H in limiting chronic pulmonary neutrophilic inflammation. Science. 330(6000):90-4.

Snelgrove RJ, Goulding J, Didierlaurent AM, Lyonga D, Vekaria S, Edwards L, Gwyer E, Sedgwick JD, Barclay AN, Hussell T (2008). A critical function for CD200 in lung immune homeostasis and the severity of influenza infection. Nature Immunology. 9(9):1074-83

Didierlaurent A, Goulding J, Patel S, Snelgrove R, Low L, Bebien M, Lawrence T, van Rijt LS, Lambrecht BN, Sirard JC, Hussell T(2008). Sustained desensitization to bacterial Toll-like receptor ligands after resolution of respiratory influenza infection. The Journal of Experimental Medicine. 205(2):323-9.

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