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I-Domain of Lymphocyte Function-Associated Antigen-1 Mediates Rolling of Polystyrene Particles on ICAM-1 under Flow

A. Omolola Eniola ^* , Ellen F. Krasik  , Lee A. Smith ^* , Gang Song  and Daniel A. Hammer ^*  

^* Department of Chemical and Biomolecular Engineering, Department of Bioengineering, and Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, Pennsylvania 19104; and CBR Biomedical Research Institute, Harvard Medical School, Boston, Massachusetts 02115

Correspondence: Address reprint requests to Daniel A. Hammer, Dept. of Bioengineering, University of Pennsylvania, 120 Hayden Hall, 3320 Smith Walk, Philadelphia, PA 19104. Tel.: 215-573-6761; Fax: 215-573-2071; E-mail: hammer{at}seas.upenn.edu.

In their active state, ß₂-integrins, such as LFA-1, mediate the firm arrest of leukocytes by binding intercellular adhesion molecules (ICAMs) expressed on endothelium. Although the primary function of LFA-1 is assumed to be the ability to mediate firm adhesion, recent work has shown that LFA-1 can contribute to cell tethering and rolling under hydrodynamic flow, a role previously largely attributed to the selectins. The inserted (I) domain of LFA-1 has recently been crystallized in the wild-type (wt) and locked-open conformations and has been shown to, respectively, support rolling and firm adhesion under flow when expressed in _Lß₂ heterodimers or as isolated domains on cells. Here, we report results from cell-free adhesion assays where wt I-domain-coated polystyrene particles were allowed to interact with ICAM-1-coated surfaces in shear flow. We show that wt I-domain can independently mediate the capture of particles from flow and support their rolling on ICAM-1 surfaces in a manner similar to how carbohydrate-selectin interactions mediate rolling. Adhesion is specific and blocked by appropriate antibodies. We also show that the rolling velocity of I-domain-coated particles depends on the wall shear stress in flow chamber, I-domain site density on microsphere surfaces, and ICAM-1 site density on substrate surfaces. Furthermore, we show that rolling is less sensitive to wall shear stress and ICAM-1 substrate density at high density of I-domain on the microsphere surface. Computer simulations using adhesive dynamics can recreate bead rolling dynamics and show that the mechanochemical properties of ICAM-1-I-domain interactions are similar to those of carbohydrate-selectin interactions. Understanding the biophysics of adhesion mediated by the I-domain of LFA-1 can elucidate the complex roles this integrin plays in leukocyte adhesion in inflammation.

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