Leukocyte adhesion must be tightly controlled for leukocytes to patrol the body as non-adherent cells, yet stop and emigrate from the blood into tissues at sites of infection or inflammation. This involves control adhesiveness of both the leukocyte and the endothelial cell to which it adheres. While some of this control consists of regulation of expression of adhesion molecules, more rapid regulation also occurs. On leukocytes, adhesiveness is increased as integrins are rapidly rearranged into clusters. However, rapid (seconds to minutes) rearrangement of adhesion receptors is not a feature of most cell types. Endothelial cells, like leukocytes, regulate their adhesiveness rapidly, so receptor rearrangement may play a role. It was recently demonstrated that ICAM-1 clusters in response to activating signals. Whether this clustering occurs before, during, or after leukocyte binding is not known, and will have consequences for the role these receptor movements in regulation of inflammation. Dimerization of ICAM-1 is known to greatly increase binding to its counter-receptors, but the effect of higher-order clustering has not been tested. Our hypothesis is that, as with integrins on leukocytes, rearrangement of adhesion molecules on endothelial cells regulates leukocyte adhesion. We will focus on ICAM-1 to test this hypothesis by completion of the following specific aims.
Aim 1 : Determine the time course and mechanism (diffusion vs cytoskeletal transport) of ICAM-1 rearrangement in response to cytokine stimulation and receptor engagement.
Aim 2 : Determine the effects of ICAM-1 clustering and cytoskeletal linkage on leukocyte adhesion under flow. If our hypothesis proves true, this new role for adhesion molecule rearrangement on endothelial cells would represent a novel level of regulation of inflammation that could be a potential target for therapeutic intervention.
| Kucik, Dennis F; Wu, Chuanyue (2005) Cell-adhesion assays. Methods Mol Biol 294:43-54 |
| Chacko, Balu K; Chandler, Robert T; Mundhekar, Ameya et al. (2005) Revealing anti-inflammatory mechanisms of soy isoflavones by flow: modulation of leukocyte-endothelial cell interactions. Am J Physiol Heart Circ Physiol 289:H908-15 |
