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

¹ University of Pennsylvania
² Harvard Medical School

^* To whom correspondence should be addressed. E-mail: hammer{at}seas.upenn.edu.

Submitted on December 8, 2004
Revised on January 10, 2005
Accepted on 21 July 2005

	Abstract

In their active state, 2-integrins, such as LFA-1, mediate the firm arrest of leukocytes by binding intercellular adhesion molecules (ICAMs) expressed on endothelium. While 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 have been shown to, respectively, support rolling and firm adhesion under flow when expressed in L2 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 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 that 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.

Key Words: ICAM-1, LFA-1, inflammation, integrin, leukocyte, rolling

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