Abstract
Integrins are components of cell-matrix adhesions, and function as scaffolds for various signal transduction pathways. So far no lipid ligand for integrin has been reported. Here we show that a lipid, oxysterol 25-hydroxycholesterol (25HC), directly binds to α5β1 and αvβ3 integrins to activate integrin-focal adhesion kinase (FAK) signaling. Treatment of macrophages and epithelial cells with 25HC results in an increase in activated αvβ3 integrin in podosome and focal adhesion matrix adhesion sites. Moreover, activation of pattern recognition receptor on macrophages induces secretion of 25HC, triggering integrin signaling and the production of proinflammatory cytokines such as TNF and IL-6. Thus, the lipid molecule 25HC is a physiologically relevant activator of integrins and is involved in positively regulating proinflammatory responses. Our data suggest that extracellular 25HC links innate immune inflammatory response with integrin signaling.
Highlights
Integrins are components of cell-matrix adhesions, and function as scaffolds for various signal transduction pathways
We identify 25-hydroxycholesterol (25HC), an oxygenated metabolite of cholesterol catalyzed by the enzyme cholesterol 25-hydroxylase (C25H) as a lipid ligand of integrins. 25HC directly interacts with integrins to trigger focal adhesion kinase (FAK) activation
While there are a number of candidate receptors, previous reports demonstrating a role of integrin-FAK signaling in inducing proinflammatory response led us to hypothesize that activation of integrin-FAK signaling by 25HC may represent the molecular mechanism driving the proinflammatory activity of 25HC27,28
Summary
Integrins are components of cell-matrix adhesions, and function as scaffolds for various signal transduction pathways. FAs and podosomes contain many proteins, tether the cell to the extracellular matrix, function as membrane attachment sites for the actin cytoskeleton, are involved in cell motility and invasion, and act to scaffold integrin-mediated signaling events[12]. The latter are involved in numerous pathways, some of which lead to changes in gene expression via the actions of transcription factors such as MAPK and NFκB which, in turn, regulate various cellular functions, including the proinflammatory response and inflammation during innate immunity, the subject of this study[12]. Show that extracellular 25HC, released from PRR-activated cells, is a molecular link bridging the PRR pathway and integrin-FAK signaling
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