Inflammation ‘weakens’ immune cells in the brain

Although microglial cells, which represent the first line of immune defense in the central nervous system, constantly mechanically interact with their environment, our current understanding of microglia mechanics is very limited. Here, we quantified forces exerted by healthy and activated microglial cells, investigated how mechanical signals impact their migration patterns, developed a theoretical framework to predict their mechanical behavior, and found that immune activation decreases microglial forces and enhances their migration towards stiffer substrates.

HFSP Young Investigator Grant holders Kristian Franze, Malte Gather and Giuliano Scarcelli and colleagues
authored on Tue, 10 November 2015

As the central nervous system is separated from the immune system of the body by the blood–brain barrier, it has its own cells that are in charge of fighting infections and pathological processes: microglial cells. These cells are highly motile and, like many other cells in the developing and regenerating nervous system, constantly move. In order to move, cells need to exert forces on their environment and mechanically interact with it. Although force generation is fundamental for microglia function, these forces have never been measured, and how microglia interact with their mechanical environment is currently poorly understood. Investigating such forces and mechanical interactions of cells in the nervous system is the core of the authors’ HFSP grant.

Figure: The image shows traction forces of a microglial cell, whose outline is shown.  Arrows point in the direction of local forces, color codes the force magnitude: red indicates large forces, while blue represents areas of small forces.

We quantified forces exerted by microglial cells on their environment and found that microglia are much stronger than neurons and that they pull harder on stiffer substrates. However, when exposed to lipopolysaccharide, which is found in the cell wall of certain bacteria, and which is known to trigger an immune response in microglia, forces exerted by the cells decreased.

As neural tissue is mechanically highly heterogeneous, motile microglia often encounter stiffness gradients in the tissue. As not only the forces of microglial cells but also their morphology and cytoskeletal structures depended on the stiffness of their environment, we tested how cell motility is impacted by a local change in substrate stiffness. When cultured on substrates incorporating stiffness gradients, microglia migrated towards the stiffer side of the substrate, a process termed ‘durotaxis’. Immune-activation by lipopolysaccharide not only increased their migration velocity but also enhanced durotaxis. We finally developed a mathematical model, which connects the cells’ traction forces with their durotactic behavior.

Our study sheds the first light on how microglial cells mechanically interact with their environment. These mechanical interactions might not only be important for the everyday function of microglial cells but they might also be critically involved in several different pathologies of the nervous system. The change in mechanical brain tissue properties encountered in many different pathological processes of the nervous system, for example, could significantly alter microglial function and thus contribute to the progression of the disease. Understanding the mechanics of microglia will thus provide a more holistic understanding of their function and ultimately reveal new insights into disorders of the nervous system.

The work represents one component of a broader project funded by HFSP in 2013 that integrates expertise in optics, biophysics and neurobiology to investigate the role of mechanics in CNS development.  While our understanding of the biochemical and molecular control of processes in the central nervous system is increasing rapidly, the contribution of the dynamic interplay between cellular forces and tissue elasticity remains poorly understood – mostly due to a lack of suitable measurement techniques.

To address this need, in this interdisciplinary project, a novel photonic toolbox is developed for in situ, label-free and non-contact measurements of cellular forces and elasticity.  Force sensing (developed in the lab of Dr. Malte Gather at the University of St. Andrews, UK) is based on spatially mapping nanoscale deformations of an ultra-flexible planar optical microcavity in response to local stress. Elasticity measurements (developed in the lab of Dr. Scarcelli, at the University of Maryland, USA) is based on the high-resolution Brillouin microscopy described here. Force and elasticity measurements are combined to illuminate how forces exerted by neurons contribute to axon formation and neuronal guidance (led by the lab of Dr. Kristian Franze at the University of Cambridge UK).

Reference

Microglia mechanics: immune activation alters traction forces and durotaxis. Bollmann L, Koser DE, Shahapure R, Gautier HOB, Holzapfel GA, Scarcelli G, Gather MC, Ulbricht E, and Franze K. Frontiers in Cellular Neuroscience 9:363 (2015).

Pubmed link

Light-based measurement of cell elasticity (Scarcelli lab)