My research group studies the molecular mechanisms of integrin activation in leukocytes. Integrins are a family of cell surface adhesion and signaling receptors that guide the trafficking of leukocytes during inflammation and the immune response. Intracellular proteins regulate the global structure of integrins and thus modulate their affinity for ligands expressed on the endothelial lining of blood vessels and within tissues. Our lab employs intravital imaging (in vivo video microscopy) to observe the inflammatory response within the living tissue as it is occurring. We also employ microfluidic flow chambers to quantify leukocyte behavior (rolling, adhesion and migration) on defined substrates.
We have several ongoing projects. Lauren Watts, a graduate student in the Pathobiology program, is studying how the integrin receptor Mac-1 is activated and the role it plays in neutrophil rolling and adhesion during inflammation. In addition, our research assistant, Feng Feng, is developing fluorescent probes to perform live subcellular imaging of primary neutrophils. Finally, having recently described how two signaling proteins that activate integrins, Talin-1 and Kindlin-3, regulate leukocyte rolling and adhesion, the Lefort lab is digging further to determine whether these molecules play additional roles in leukocyte transmigration across the blood vessel barrier.
Additional Research Interests
Neutrophil recruitment in the lungs occurs in a manner distinct from that observed in other tissues in the body. In response to certain inflammatory insults, neutrophils which normally use integrin receptors to adhere to the blood vessel wall can instead become trapped in the narrow capillaries of the lung airways without using integrins. We are taking advantage of this physiological anomaly to ask whether subsequent steps of neutrophil recruitment -- crossing the endothelial cell, basement membrane, and epithelial cell barriers -- requires the use of integrins and whether their activation is necessary. This could have implications in treating acute lung injury or may provide insight as to whether anti-inflammatory therapies targeting activated integrins would still preserve lung immunity.
- Video #1 - K562/PSGL1 cell rolling. K562/PSGL1 cells rolling on P-selectin in a microfluidic flow chamber.
- Video #2 - Leukocyte rolling in mouse cremaster venules. Leukocytes (primarily neutrophils) rolling via P-selectin in a post-capillary venule of a mildly inflamed mouse cremaster muscle prep.
- Video #3 - Leukocyte rolling in TNFa-treated mouse cremaster venules. Leukocytes (primarily neutrophils) rolling and adherent in a post-capillary venule of a mouse cremaster muscle prep treated with TNFa to induce inflammation.