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Published on: May 19, 2016
Macrophage motility requires distinct α5β1/FAK and α4β1/paxillin signaling events
Michelle Y Abshire1, Keena S Thomas, Katherine A Owen
1Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Abstract:
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 β1 integrin heterodimers expressed in these cells-α4β1 and α5β1. We show that α4β1 and α5β1 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 α5β1 for haptotaxis toward FN and chemotaxis toward M-CSF-1 and downstream of α4β1 for the adoption of a polarized phenotype. The scaffolding molecule paxillin functions independently of FAK to promote chemotaxis downstream of α4β1. These studies expand our understanding of β1 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.
Insights
This study reveals how specific integrins (α4β1, α5β1) and FAK regulate macrophage movement and invasion during inflammation. Understanding these pathways offers new insights into macrophage functions.
Area of Science:
- Cell Biology
- Immunology
Background:
- Macrophages are crucial inflammatory mediators involved in infection and tissue repair.
- Integrin and growth factor receptors mediate monocyte/macrophage recruitment via extracellular stimuli.
- Focal Adhesion Kinase (FAK) is implicated in regulating macrophage chemotaxis and invasion.
Purpose of the Study:
- To elucidate the molecular mechanisms of FAK and β1 integrin heterodimers (α4β1, α5β1) in macrophage motility.
- To define the signaling pathways governing macrophage invasion and polarization.
Main Methods:
- Investigated the roles of α4β1 and α5β1 integrins in macrophage haptotaxis and chemotaxis.
- Assessed the requirement of FAK downstream of α5β1 and α4β1 integrins.
- Examined the function of paxillin in relation to FAK and α4β1 signaling.
Main Results:
- α4β1 and α5β1 integrins are essential for efficient macrophage haptotactic and chemotactic invasion.
- Integrin stimulation induces distinct macrophage morphologies related to motility.
- FAK is required downstream of α5β1 for haptotaxis and downstream of α4β1 for polarization.
- Paxillin promotes chemotaxis downstream of α4β1, independent of FAK.
Conclusions:
- These findings enhance the understanding of β1 integrin signaling networks regulating macrophage motility and invasion.
- Provides novel insights into the mechanisms underlying diverse macrophage functions in inflammatory contexts.
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