Microglia mechanics: immune activation alters traction forces and durotaxis.

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Bollmann, Lars 
Koser, David E 
Shahapure, Rajesh 
Gautier, Hélène OB 
Holzapfel, Gerhard A 

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.

CNS, LPS, biased random walk, foreign body reaction, gliosis, mechanotaxis, migration, random walk
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Front Cell Neurosci
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Frontiers Media SA
Medical Research Council (G1100312)
Human Frontier Science Program (HFSP) (RGY0074/2013)
Leverhulme Trust (RPG-2014-217)
Isaac Newton Trust (1407(m))
The authors thank Daniel Koch for providing software for traction force microscopy analysis, Kimberley Evans, Ragnhildur Thora Karadottir, and James Fawcett for help with microglial cells, Berenike Maier, Ulrich Schwarz, Timo Betz, Ivana Cvijovic, and Emad Moeendarbary for helpful discussions and technical support. This work was supported by the Austrian Agency for International Cooperation in Education and Research (Scholarship to LB), Faculty of Computer Science and Biomedical Engineering at Graz University of Technology (Scholarship to LB), German National Academic Foundation (Scholarship to DK), Wellcome Trust/University of Cambridge Institutional Strategic Support Fund (Research Grant to KF), Isaac Newton Trust (Research Grant 14.07 (m) to KF), Leverhulme Trust (Research Project Grant RPG-2014-217 to KF), UK Medical Research Council (Career Development Award to KF), and the Human Frontier Science Program (Young Investigator Grant RGY0074/2013 to GS, MG, and KF).