Lung immunity in health and disease

Principal Investigator and MCCIR Director

Professor Tracy Hussell
Tel: +44 (0)161 275 1537
Email: tracy.hussell@manchester.ac.uk

Our research

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.

Alveolar macrophages

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.

Epithelial and alveolar macrophage interactions

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.