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Substrate Stiffness Regulates Proinflammatory Mediator Production through TLR4 Activity in Macrophages
Michelle L Previtera1,2, Amitabha Sengupta1
1JFK Neuroscience Institute, JFK Medical Center, 65 James Street, Edison, New Jersey, 08820, United States of America.
Plos One
|December 29, 2015
Summary
Tissue stiffness significantly impacts macrophage inflammatory responses. Macrophages on stiffer surfaces produced more pro-inflammatory mediators via the Toll-like receptor 4 (TLR4) pathway, suggesting mechanical regulation of inflammation.
Area of Science:
- Biomedical Engineering
- Immunology
- Cell Biology
Background:
- Disease negatively impacts tissue elasticity and stiffness.
- Macrophage activity is crucial in disease pathology.
- Limited data exist on how tissue stiffness influences macrophage activity.
Purpose of the Study:
- Investigate the effects of substrate stiffness on macrophage inflammatory mediator production.
- Explore the molecular pathways involved in stiffness-regulated inflammation.
Main Methods:
- Cultured bone marrow-derived macrophages on polyacrylamide gels of varying stiffness.
- Stimulated macrophages with lipopolysaccharide (LPS).
- Assessed inflammatory mediator production and Toll-like receptor 4 (TLR4) signaling pathway components (TLR4, p-NF-κB p65, MyD88, p-IκBα) expression and translocation.
- Conducted TLR4 knockout experiments.
Main Results:
- Macrophages on soft substrates produced fewer pro-inflammatory mediators than those on stiff substrates upon LPS stimulation.
- Expression and translocation of TLR4 signaling molecules were elevated on stiff substrates.
- TLR4 activity amplified pro-inflammatory responses on stiff substrates.
Conclusions:
- Pro-inflammatory mediator production by macrophages, initiated by TLR4, is mechanically regulated by substrate stiffness.
- Tissue stiffness is a critical factor influencing macrophage-mediated inflammation.
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