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.