Substrate Viscoelasticity Amplifies Distinctions between Transient and Persistent LPS-Induced Signals

Area of Science:

• Immunology
• Biophysics
• Cell Biology

Background:

• Macrophages are key immune cells residing in diverse microenvironments.
• Chemical cues are known to regulate macrophage behavior, but the role of viscosity is overlooked.
• Viscosity changes in tissues, increasing in inflammation but not tumors, impacting immune responses.

Purpose of the Study:

• To investigate the impact of substrate viscoelasticity on macrophage activation and inflammatory responses.
• To understand how viscosity modulates transcriptional programs and immune cell behavior under different stimulation durations.
• To identify the molecular mechanisms, including transcription factors and cytoskeletal dynamics, involved in viscosity-mediated immune regulation.

Main Methods:

• Utilized lipopolysaccharide (LPS) to stimulate macrophages on elastic and viscoelastic substrates.
• Analyzed transcriptional profiles and actin filament (F-actin) dynamics.
• Investigated the role of transcription factors NF-κB, C/EBPδ, and ATF3.
• Applied a clutch-like model to predict F-actin fluctuations.

Main Results:

• Viscoelastic substrates amplified inflammatory responses under persistent LPS stimulation compared to transient stimulation.
• Substrate viscosity modulated distinct transient and persistent LPS-induced transcriptional programs.
• F-actin dynamics correlated with transcriptional profiles and were predictable by a clutch-like model.
• Viscosity influenced immune responses via transcription factors NF-κB and C/EBPδ, acting as infection duration switches.
• ATF3 translocation to nuclei, linked to actin nucleation, attenuated immune responses.

Conclusions:

• Substrate viscoelasticity intensifies inflammation specifically during persistent infections.
• Macrophage responses to substrate mechanics provide a mechanism for sensing infection duration.
• Findings offer insights into immune responses in inflammatory and cancerous microenvironments.
• This research has potential applications in regulating inflammatory processes.