Microglia mechanics: immune activation alters traction forces and durotaxis
Lars Bollmann1, David E Koser2, Rajesh Shahapure3
1Department of Physiology, Development and Neuroscience, University of Cambridge Cambridge, UK ; Faculty of Computer Science and Biomedical Engineering, Institute of Biomechanics, Graz University of Technology Graz, Austria.
Abstract:
Microglial cells are key players in the primary immune response of the central nervous system. They are highly active and motile cells that chemically and mechanically interact with their environment. While the impact of chemical signaling on microglia function has been studied in much detail, the current understanding of mechanical signaling is very limited. When cultured on compliant substrates, primary microglial cells adapted their spread area, morphology, and actin cytoskeleton to the stiffness of their environment. Traction force microscopy revealed that forces exerted by microglia increase with substrate stiffness until reaching a plateau at a shear modulus of ~5 kPa. When cultured on substrates incorporating stiffness gradients, microglia preferentially migrated toward stiffer regions, a process termed durotaxis. Lipopolysaccharide-induced immune-activation of microglia led to changes in traction forces, increased migration velocities and an amplification of durotaxis. We finally developed a mathematical model connecting traction forces with the durotactic behavior of migrating microglial cells. Our results demonstrate that microglia are susceptible to mechanical signals, which could be important during central nervous system development and pathologies. Stiffness gradients in tissue surrounding neural implants such as electrodes, for example, could mechanically attract microglial cells, thus facilitating foreign body reactions detrimental to electrode functioning.
Insights
Microglial cells, crucial for central nervous system immunity, respond to mechanical cues. This study shows they sense and move towards stiffness gradients, impacting neural implant integration.
Area of Science:
- Neuroimmunology
- Cellular Mechanobiology
Background:
- Microglial cells are vital for central nervous system (CNS) immune responses.
- Their mechanical interactions with the environment are poorly understood compared to chemical signaling.
- Understanding mechanical signaling is crucial for CNS development and disease.
Purpose of the Study:
- To investigate the role of mechanical signaling in microglial cell behavior.
- To explore how substrate stiffness and gradients influence microglial morphology, force exertion, and migration.
- To model the relationship between microglial traction forces and durotaxis.
Main Methods:
- Primary microglial cells cultured on substrates with varying stiffness and stiffness gradients.
- Traction force microscopy to measure forces exerted by microglia.
- Analysis of cell morphology, spread area, and migration patterns.
- Mathematical modeling of microglial durotaxis.
Main Results:
- Microglial cells alter morphology and actin cytoskeleton based on substrate stiffness.
- Microglial force exertion increases with substrate stiffness up to ~5 kPa.
- Microglia exhibit durotaxis, migrating towards stiffer regions.
- Immune activation amplifies microglial traction forces, migration velocity, and durotaxis.
Conclusions:
- Microglial cells are sensitive to mechanical signals in their microenvironment.
- Mechanical cues, like stiffness gradients, influence microglial migration and behavior.
- These findings have implications for CNS development, pathologies, and neural implant design, potentially mitigating foreign body reactions.
