Research

The inflammatory response is a crucial element of survival. Inflammation protects the body from invading pathogens and is the first step of regeneration and wound healing after injury. All inflammatory responses start with the extravasation of leukocytes from the blood stream into affected tissues. This is often accompanied by increased vascular permeability. These processes need to be tightly regulated because if not controlled properly, a continuous inflammatory response can lead to sepsis and chronic inflammatory diseases. Thus, elucidating the molecular mechanisms that control vascular permeability and leukocyte extravasation is of utmost importance for understanding why and when an acute inflammation turns into a chronic inflammation. Although much effort has been spent on elucidating the molecular mechanisms regulating vascular permeability and leukocyte extravasation in inflammatory diseases, many details are still poorly understood. While several adhesion molecules play a key role in mediating endothelial cell contact stability and leukocyte transmigration, much less is known about the role of actin, actin-binding molecules and related intracellular signaling.

We have shown that endothelial cortactin regulates vascular permeability and neutrophil extravasation at sites of inflammation in vivo. In functional studies, we demonstrated that cortactin controls the activity of small GTPases: Rap1 is less active in cortactin-deficient cells, whereas RhoG cannot be activated upon leukocyte binding to endothelial cells. Moreover, we found that the major endothelial receptor for leukocytes, ICAM-1, cannot cluster around leukocytes without cortactin. We are now unraveling the molecular mechanisms by which cortactin regulates leukocyte extravasation and vascular permeability. We are analyzing if cortactin acts as scaffold molecule to coordinate the molecular machinery required for controlled GTPase activation. Additionally, we are examining how cortactin regulates ICAM-1 clustering to control leukocyte extravasation and whether the clustering of other important adhesion molecules such as VCAM-1 is also disturbed. Cortactin deficiency also affects the actin cytoskeleton in endothelial cells. Thus, we are analyzing actin cytoskeleton dynamics downstream of leukocyte binding and related signal transduction via RhoGTPases in more detail. 

Moreover, we are interested in the role of cortactin in regulating intestinal epithelial permeability. We are testing if cortactin plays a role in the pathogenesis of inflammatory bowel disease, a chronic relapsing inflammation of the intestines. 

In addition, we are interested in the functionality of the general immune response in the absence of cortactin after a pathogenic challenge, for example, with Salmonella enterica strains to induce a model of typhoid fever. Since leukocyte extravasation is strongly blocked without cortactin it is tempting to speculate that cortactin-deficient mice have difficulties in pathogen clearance and show a more severe disease phenotype or even die of the infection. 

We are also examining whether the cortactin homologue in leukocytes, HS1, supports leukocyte extravasation. We already found that HS1 deficiency also results in defective leukocyte recruitment and we are now elucidating the molecular mechanisms behind this effect. 

We are confident that the results of our line of research will clarify the mechanisms of cortactin-mediated signaling during the immune response and may identify cortactin as target for novel treatment strategies for chronic inflammatory disorders.