Joan Cook-Mills, PhD Associate Professor Medicine, Division of Allergy-Immunology Endothelial cell function during allergic disease Curricula: Cell Biology Immunology and Microbial Pathogenesis Molecular Biology and Genetics E-mail:   j-cook-mills@northwestern.edu

Leukocyte migration from the blood into tissues is vital for immune surveillance and inflammation.   Specificity for the site of leukocyte migration is determined by the combination of adhesion molecules, cytokines and chemokines in the microenvironment.

We have focused on the function of the endothelial cell adhesion molecule VCAM-1.  VCAM-1 is expressed on endothelial cells during atherosclerosis, allograft rejection, infection, and asthmatic responses. Furthermore, disruption of the mouse VCAM-1 gene impairs placentation and cardiac development resulting in embryo death.  Thus, VCAM-1 has important functions in development and disease.  As little was known regarding VCAM-1 signaling, we studied the molecular mechanisms for VCAM-1 signal transduction in endothelial cells in vitro and in vivo.

Although it had traditionally been thought that VCAM-1 simply serves as a scaffold for leukocyte binding to endothelium, we have reported that it activates endothelial cell intracellular signal transduction pathways which result in endothelial cell shape changes and leukocyte passage. VCAM-1 activates endothelial cell NADPH oxidase resulting in the generation of low non-toxic levels of reactive oxygen species (ROS).  These ROS rapidly stimulate endothelial cell-associated matrix metalloproteinases (MMP) and protein kinase C which are required for VCAM-1-dependent lymphocyte migration. We have also demonstrated that, during allergic asthma, VCAM-1-dependent leukocyte recruitment in vivo is blocked in NOX2 knockout mice and blocked by administration of the antioxidant bilirubin.

Currently, there are two main research directions. 

1. We are examining mechanisms for VCAM-1-stimulated activation of endothelial cell NADPH oxidase, including studies of the structure/function of the cytoplasmic tail of VCAM-1.  We are also examining the mechanisms for ROS and protein kinase C in regulating endothelial cell intracellular signals.

2.  To further determine whether these VCAM-1 signals function in vivo, we are utilizing knockout and transgenic mouse models to examine VCAM-1-dependent infiltration of eosinophils in experimental asthma.  Pulmonary eosinophilia is one of the most consistent hallmarks of asthma.

3. We are examining vitamin E isoforms for their function as antioxidants and immunoregulatory molecules in allergic asthma.  We are using both mouse models and clinical samples to examine vitamin E function in asthma.  We have identified novel properties of vitamin E isoforms that have lead to reinterpretation of the literature on vitamin E in disease.

Information about the mechanisms that control leukocyte infiltration will provide a basis towards proposing interventions in VCAM-1-mediated processes in disease.    Moreover, limiting VCAM-1 dependent inflammation in chronic disease may be an advantageous target as it would spare VCAM-1-independent inflammation such as neutrophil clearance of infections.

Selected Publications:

View Publications by Joan Cook-Mills listed in the National Library of Medicine (PubMed).

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