Grant: Operating Grant

Idiopathic pulmonary fibrosis (IPF) affects 5 million people with a mean survival time 2-3 years after diagnosis. Lung fibrosis is a dysregulated reparative response to micro-injuries leading to excessive deposition and stiffening of collagen matrix. This scar tissue destroys the delicate lung architecture, decreases lung compliance and gas exchange, ultimately rendering patients unable to breathe. The only effective treatment for IPF patients is a lung transplant. Typical of lung fibrosis is the chronic co-existence of connective tissue fibroblasts, and inflammatory cells, macrophages. This scenario differs from normal tissue repair, where macrophages appear first to remove tissue debris and dead cells before they summon fibroblasts. Macrophages leave cues in the matrix that instruct fibroblasts to provide matrix as 'tissue glue'. The by far most important fibroblast instructor is the growth factor TGF-b1.We propose that tissue repair ends when all the TGF-b1 is consumed by fibroblastic cells (normal) but continues if macrophages do not disappear as planned (fibrosis) and provide continuous TGF-b1 supply. The question is why macrophages do not disappear in fibrosis? We have identified cadherin-11 as a protein on the surface of myofibroblasts and macrophages that promotes specific attachment of both cell types. We will investigate the mechanisms of how cadherin-11 mediates persistence of both fibrotic cells. We will further decipher how the continuous presence of macrophages and myofibroblasts affects the activation state of both cells. Finally, we will pursue initial results showing that cell-cell attachment creates an intimate couple where macrophages directly present inactive TGF-b1 for myofibroblasts to activate and to interpret as repair signal. It is our ultimate aim to terminate pro-fibrotic signalling by specifically separating this couple of cells that are beneficial when acting on their own but turning bad when getting too close.