Role of a Novel Scavenger Receptor in Epithelial Inflammatory Responses

The immune system protects us from infection. When we are exposed to an infection for the first time the so-called ?innate? immune system is responsible for detecting and responding to bacteria and viruses and other particles that enter the body. The innate system also serves help the so-called ?acquired? immune system, which prevents re-infection. One activity of innate immune is the generation of an inflammatory response. This is important for fighting infection, but if this response is not controlled properly severe disease results (for example, asthma and chronic obstructive inflammatory disease in the lung).The functioning of innate immune system is dependent upon the expression of molecules on the surface of immune system cells, known as pattern recognition receptors. These molecules are able to sense pathogens and trigger an appropriate immune response to get rid of the infection. Because of its large surface area, the lung is a major site where disease-causing airborne microbes and other agents enter the body. The lung is lined by specialised cells (epithelial cells), which provide not only a physical barrier but also play an important role in innate immunity (e.g. they produce substances that help kill bacteria). However, we have a very limited understanding of these pattern recognition receptors they express and how they function to keep the lung healthy.
In this grant, we propose to study a newly identified epithelial-specific pattern recognition receptor and see how it is involved in epithelial inflammatory responses. This receptor is only expressed on certain epithelial cells, including some within the lung. We will investigate the nature of pro-inflammatory agents it can recognise and the consequences of altering the expression of the receptor on epithelial inflammatory responses. This research will help us to understand how the health of the lung is normally maintained and what may go wrong in specific disease conditions. It may also reveal new ways to treat inflammatory lung diseases.

We aim to study the contribution of a novel pattern recognition receptor (PRR) to the regulation of inflammatory responses of airway epithelia. Epithelia separate the internal milieu of the host from the external environment, present a physical barrier to the entry of pathogens and play crucial roles in initiating and augmenting host defense mechanisms. Because of its very large surface area, the human lung is exposed to great volumes of pathogens and other noxious substances via inhalation that have the capacity to induce damaging inflammatory reactions. These agents also can exacerbate underlying inflammatory conditions, such as asthma and chronic obstructive pulmonary disease. Epithelia play a pivotal role in the induction of lung inflammation and injury. However, despite the important contributions of respiratory epithelial cells, our understanding of the mechanisms that regulate their inflammatory responses is relatively poor.
Recently, we identified a novel PRR, a scavenger receptor (SCARA5) that uniquely is epithelial-restricted. Scavenger receptors display unusually broad ligand binding properties. We hypothesise that SCARA5 has important roles in the innate immune activities of epithelia. We have shown in preliminary experiments SCARA5 can recognise lipopolysaccharide (LPS), a component of Gram-negative bacteria and important immunostimulant of innate immune cells. Through the application of anti-SCARA5 antisera we have confirmed that epithelial cell lines that have characteristics of respiratory epithelia express the receptor. We have generated by genetic engineering a mouse strain deficient in SCARA5, which will facilitate studies in vivo and ex-vivo. We hypothesise that SCARA5 is a PRR on airway epithelia that significantly influences their pro-inflammatory responses to LPS and other specific stimuli.
In this proposal we will exploit these data and will address the following questions:
1. What is the diversity of pro-inflammatory molecules recognised by the receptor?
2. Does receptor engagement stimulate specific signalling pathways?
3. Do changes in relative levels of receptor alter epithelial inflammatory responses?
4. How does the receptor influence the cellular uptake and fate of specific pro-inflammatory molecules?
5. What is the pattern of cellular expression of the receptor in vivo?
This programme of research will significantly expand our understanding of the innate immune mechanisms of airway epithelia and has the potential to identify roles for this PRR in pathological processes that may be a therapeutic target.