Macrophage PPAR gamma signalling and exaggerated inflammation in CGD. Professor Donna Bratton and Dr Ruby Fernandez-Boyanapalli, National Jewish Health, Denver, USA, £105,379 over two years.

This project will examine the cellular mechanisms leading to inflammation in CGD. The work will study the recognition and clearance of dying neutrophils and resulting anti-inflammatory signalling that fail to work properly in CGD leading to excessive inflammation. The group will test new ways to ensure that normal signalling is restored so that inflammatory problems in CGD are avoided.

'We know that neutrophils are recruited from the blood into tissues following infection or injury. Once the recruited neutrophils have dealt with the infection or injury, they die in a manner that allows them to be recognised by cells called macrophages, which 'eat' them and recycle their components. This process stimulates the macrophages to signal that further recruitment of new neutrophils should stop and tissues should heal', explains Professor Bratton. 'However, in CGD, this does not happen and we see excessive inflammation and tissue damage. We know that CGD neutrophils do not signal to macrophages for ingestion and recycling. Instead they decompose and the cell products cause more tissue injury and autoimmunity', stated Professor Bratton. 'We are starting to understand more about how the interplay leads to damaging inflammation.' The study will investigate further two key signals that don't work properly in this system and will test new ways to restore proper functioning in CGD macrophages and neutrophils so that clearing of dead cells occurs and excessive inflammation is avoided. 'We are going to use a CGD mouse model to test two different ways of overcoming the problems of signalling between macrophages and neutrophils. One involves testing a drug currently being used to treat other conditions in the context of CGD. We think these treatments may help normalise clearance of dying cells, and will significantly inhibit the production of inflammatory signals that lead to exaggerated inflammation in CGD,' stated Professor Bratton. The group is renowned for its work in this area and the Trust is investing £105,000 over two years to support a post-doctoral fellow in this project.