Adhesive Dynamics Simulation of Neutrophil Arrest with Deterministic Activation

¹ University of Pennsylvania
² U. Pennsylvania

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

Submitted on July 20, 2005
Revised on September 8, 2005
Accepted on 3 March 2006

	Abstract

The transition from rolling to firm adhesion is a key element of neutrophil activation and essential to the inflammatory response. Although the molecular mediators of rolling and firm adhesion are known to be selectins and ₂-integrins, respectively, the precise dynamic mechanism by which these ligands facilitate neutrophil arrest remains unknown. Recently, it has been shown that ligation of E-selectin can stimulate the firm adhesion of neutrophils via a MAP-kinase cascade (1). In order to study the possible mechanism by which neutrophil arrest could occur, we create an integrated model by combining two methodologies from computational biology: a mechanics-based modeling of leukocyte adhesion (adhesive dynamics) and signal transduction pathway modeling. Within adhesive dynamics, a computational method our group has shown to accurately recreate rolling dynamics, we include a generic, tunable integrin activation module that links selectin engagement to integrin and activity. This model allows us to relate properties of the activation function to the dynamics of rolling and the time and distance rolled before arrest. This integrated model allows us to understand how intracellular signaling activity can set the time-scale of neutrophil activation, adhesion, and diapedesis.

Key Words: LFA-1, Leukocytes, MAP-kinase, integrin, neutrophils, systems biology

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