Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events

Macrophages function as key inflammatory mediators at sites of infection and tissue damage. Integrin and growth factor receptors facilitate recruitment of monocytes/macrophages to sites of inflammation in response to numerous extracellular stimuli. We have shown recently that FAK plays a role in regulating macrophage chemotaxis and invasion. As FAK is an established downstream mediator of integrin signaling, we sought to define the molecular circuitry involving FAK and the predominant beta 1 integrin heterodimers expressed in these cells-alpha 4 beta 1 and alpha 5 beta 1. We show that alpha 4 beta 1 and alpha 5 beta 1 integrins are required for efficient haptotactic and chemotactic invasion and that stimulation of these integrin receptors leads to the adoption of distinct morphologies associated with motility. FAK is required downstream of alpha 5 beta 1 for haptotaxis toward FN and chemotaxis toward M-CSF-1 and downstream of alpha 4 beta 1 for the adoption of a polarized phenotype. The scaffolding molecule paxillin functions independently of FAK to promote chemotaxis downstream of alpha 4 beta 1. These studies expand our understanding of beta 1 integrin signaling networks that regulate motility and invasion in macrophages and thus, provide important new insights into mechanisms by which macrophages perform their diverse functions. J. Leukoc. Biol. 89: 251-257; 2011.