Influence of epidermal growth factor receptor ligands in wound healing and fibrosis

Abstract

Restoration and maintenance of tissue homeostasis following injury and during inflammation is a crucial function of the immune system. The Epidermal Growth Factor Receptor (EGFR) and two of its leukocyte-derived ligands, Amphiregulin (AREG) and HB-EGF, have a well-documented role in this process and are known to contribute to wound repair as well as fibrosis. However, the underlying mechanisms by which these growth factors contribute to these processes had so far not been elucidated and my PhD was aimed to determine these mechanisms. In Chapter 2 and the appendix of my thesis, using acute tissue injury in two different organs (the liver and the lungs) we show that AREG induces the activation of integrin-alphaV complexes and thereby the local release of bio-active TGF-β on mesenchymal stromal cells also termed as pericytes. This induces the differentiation of pericytes into myofibroblasts, facilitating the restoration of blood vessel integrity following acute injury. In Chapter 3 of my thesis, I used a model of repetitive injury on the liver to induce chronic inflammation. It has been published that the two EGFR ligands- AREG and HB-EGF that are up-regulated during inflammation play antagonistic roles in the development of liver fibrosis. My data using bone marrow chimeric mice suggest that ‘leukocyte-derived’ AREG and HB-EGF display a trend towards liver remodelling during chronic inflammation. However, Kupffer cell derived AREG may not be contributing to collagen expression. Like the acute injury models, AREG appears to target EGFR on pericytes reducing the collagen deposition in the pericyte specific EGFR knockout mice. Interestingly, HB-EGF also targets primary pericytes, preventing their in vitro differentiation and may thereby reduce collagen expression. Finally, in Chapter 4 of my thesis, I focused on the role of AREG in a model of lung remodelling induced by ovalbumin-mediated chronic lung inflammation. Using global as well as different cell type-specific AREG-deficient mice, I showed that leukocyte derived AREG influences lamina propria thickness- a measure of remodelling. Likewise, AREG appears to direct lung remodelling via the EGFR on pericytes. Taken together, my thesis unravels a novel mechanism acting via the AREG-EGFR axis that controls the differentiation of tissue residential precursor cells ultimately governing wound healing as well as tissue remodelling.