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Integrin activation by the lipid molecule 25-hydroxycholesterol induces a proinflammatory response.
Swechha M Pokharel1, Niraj K Shil1, Jeevan B Gc2
1Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, 99163, USA.
Nature Communications
|April 2, 2019
Summary
The lipid 25-hydroxycholesterol (25HC) directly activates integrins, initiating signaling pathways crucial for inflammation. This discovery links innate immunity to integrin function, revealing 25HC as a key inflammatory mediator.
Area of Science:
- Cell Biology
- Immunology
- Biochemistry
Background:
- Integrins are critical cell-matrix adhesion proteins and signal transduction scaffolds.
- No lipid ligands for integrins had been previously identified.
- Oxysterols, like 25-hydroxycholesterol (25HC), are cholesterol metabolites with diverse biological roles.
Purpose of the Study:
- To investigate if oxysterols can act as ligands for integrins.
- To determine the functional consequences of 25HC binding to integrins.
- To explore the role of 25HC in innate immune inflammatory responses.
Main Methods:
- Direct binding assays to assess 25HC interaction with α5β1 and αvβ3 integrins.
- Cell treatments with 25HC in macrophages and epithelial cells.
- Analysis of integrin activation, focal adhesion kinase (FAK) signaling, and cytokine production (TNF, IL-6).
- Investigation of 25HC secretion upon pattern recognition receptor activation.
Main Results:
- 25-hydroxycholesterol (25HC) directly binds to α5β1 and αvβ3 integrins.
- 25HC treatment activates integrin-FAK signaling pathways.
- Activated αvβ3 integrin increases in podosome and focal adhesion sites upon 25HC treatment.
- Macrophage activation leads to 25HC secretion, triggering integrin signaling and proinflammatory cytokine production (TNF, IL-6).
Conclusions:
- The lipid molecule 25HC is a novel, physiologically relevant activator of integrins.
- 25HC positively regulates innate immune inflammatory responses by linking them to integrin signaling.
- Extracellular 25HC serves as a molecular bridge between innate immunity and integrin-mediated cellular processes.
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