Rolling

Once leukocytes are captured, they may transiently adhere to the venular endothelium and begin to roll. Rolling occurs at or below the velocity of freely flowing cells like erythrocytes in the same vessel and the same radial position. The velocity separating rolling from freely flowing cells is called critical velocity or hydrodynamic velocity. The selectin family of transmembrane adhesion receptors mediates this rolling process. P-selectin is the most important selectin involved in rolling. P-selectin can support both capture and rolling in the absence of L-selectin. Although P-selectin was initially identified on activated platelets, it is also found in Weibel-Palade bodies of human endothelial cells. Upon stimulation by trauma, P-selectin is rapidly surface-expressed on the venular endothelium, and it makes the endothelium "sticky" to leukocytes. PSGL-1 (P-Selectin Glycoprotein Ligand-1) is constitutively expressed on all lymphocytes, monocytes, eosinophils, and neutrophils. PSGL-1 on neutrophils, eosinophils, and monocytes has a glycosylation pattern allowing it to bind to endothelial P-selectin. As a result, the leukocyte rolls along the endothelium. During rolling, bonds are formed at the leading edge of the rolling cell and broken at the trailing edge. Leukocyte integrins initially remain in their resting state, and endothelial immunoglobulins remain at control levels.

The critical role of P-selectin in the rolling phase of the adhesion cascade is supported in experiments done on gene-targeted mice. In mice lacking P-selectin, leukocytes do not roll on the venular endothelium after surgical trauma. Also, when compared with wild-type mice, the number of circulating granulocytes is greater in P-selectin deficient mice. This suggests that P-selectin is necessary to remove the leukocytes from the bloodstream so they may stick and roll along the venular endothelium. In vitro, isolated human granulocytes have been shown to roll on purified P-selectin using flow chamber systems.

L-selectin and E-selectin also take part in the rolling process. When P-selectin is absent, trauma-induced rolling becomes L-selectin dependent, but the average leukocyte rolling velocity is three to five times faster in this case. This suggests that L-selectin is much less efficient than P-selectin in mediating the rolling process. However, L-selectin is necessary for the normal inflammatory response in capturing leukocytes and initiating rolling. An apparent redundancy exists between P- and E-selectin in mediating leukocyte rolling on cytokine-activated endothelium. E-selectin is thought to be responsible for slow rolling interactions below 5mm/s and possibly the initiation of firm adhesion.

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