|Eniolola-Adefeso, Omolola -|
|Huang, Ryan -|
|Smith, Wayne -|
Submitted to: Annals of Biomedical Engineering
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: January 20, 2009
Publication Date: January 28, 2009
Citation: Eniolola-Adefeso, O., Huang, R.B., Smith, W.C. 2009. Kinetics of LFA-1 mediated adhesion of human neutrophils to ICAM-1-role of E-selectin signaling post-activation. Annals of Biomedical Engineers. 37(4):737-748. Interpretive Summary: Among the earliest responses of the body to a high fat diet is the activation of a type of white blood cell called neutrophils. This activation increases the ability of these cells to stick to the cellular lining of blood vessels as a part of the inflammation induced by high fat diets. We studied one of the adhesion molecules on the neutrophil’s surface; a molecule called CD11a, and found that it can be rapidly activated to become sticky. This activation may be very short-lived or prolonged depending on which molecules it encounters on the blood vessel lining. This is new and very basic information that is necessary for future experiments designed to control harmful inflammation associated with obesity.
Technical Abstract: LFA-1 and Mac-1 are the two integrins involved in the arrest and firm adhesion of neutrophils. LFA-1 plays a role in the early stage of cell arrest while Mac-1 stabilizes firm adhesion. Here, we further elucidated the kinetics of LFA-1 activation and its role in mediating neutrophil adhesion to ICAM-1 in the presence of E-selectin interaction. We confirm that LFA-1 activation to high affinity is transient in nature, decaying back to low affinity within 1 min after chemotactic stimulation. However, we show for the first time that this downshift in LFA-1 affinity does not return back to the low affinity state when E-selectin interaction is present and active, but rather E-selectin signals an intermediate LFA-1 conformation through PI3-Kinase that maintains an intermediate level of neutrophil firm adhesion. We further show that this E-selectin signaling is capable of returning LFA-1 to the intermediate affinity conformation outside the 1-min window previously reported for LFA-1 functionality. While our work confirms a role for PI3-Kinase in neutrophil firm adhesion, we show that PI3-Kinase may not be important in the initial transition from rolling to firm arrest (i.e. LFA-1 shift from low to high affinity conformation occurring within seconds of chemotactic stimulation).