Innate sensing of mechanical properties of brain tissue by microglia

Abstract

External organic or inorganic objects (foreign bodies) that are inadvertently or purposefully placed in the human or animal tissues can trigger local tissue responses that aim at the elimination and/or segregation of foreign bodies from the tissue. The foreign body response (FBR) may have major implications for neurodegeneration associated with the formation of aberrant protein-based aggregates or plaques. The distinct physical features of the plaques, including high rigidity and varying surface properties, may trigger microglial mechanosensing of the plaque as a foreign body. The microglial FBR may have a dual function by promoting and/or suppressing the plaque driven neurodegeneration. Microglial contact with the plaque may trigger inflammatory activation of microglia and support microglia-driven neuronal damage. Conversely, persistent microglial activation may trigger the formation of a microglia-supported cell barrier that segregates and compacts the plaques thus preventing further plaque-induced damage to healthy neurons.

Figure 1:. Brain region specific microglia specification.

Microglia display region specific differences in morphology, density, and gene expression patterns. Schematic shows the mouse brain with digitized immunofluorescence images of IBA1+ microglia from the cortex (yellow), striatum (gray), hippocampus (green), cerebellum (red), and brain stem (black), percentages indicate the number of microglia as compared to total cell number per corresponding brain region [68,69]. A representative image of an individual cerebellar IBA1+ microglia (green) containing two large lysosomal structures (CD68: red) is shown (Imaris, DAPI: blue) [20]. Heat map shows the differential gene expression pattern of microglia by brain regions [22].

Figure 2:. Microglial response to amyloid plaques resembles macrophage response to foreign bodies.

(left) Schematic shows microglia (green) responses to amyloid plaques (orange/red), amyloid plaques are characterized by a soft lipid-rich halo (orange) surrounding the rigid core of the plaques (red), which is formed by densely folded amyloid β (Aβ) sheets [49]. (right) Representative images of IBA1+ microglia (IBA1: green) interactions with amyloid plaques (Thioflavin S (Thio S): red) in the 5xfAD mouse model [86] of Alzheimer disease are shown (DAPI+ nuclei: blue). Similar to macrophage FBR, microglia polarize and migrate toward the plaque [37], display ruffling of cell membranes and adhesion to the plaque surface, release enzymes for extracellular degradation [57], produce an inflammatory response [57], and have their processes loosely interdigitated [34-36]. The inability of microglia to clear the plaque may trigger the formation of a microglia-supported barrier leading to the physical isolation/segregation of the plaques [63,64]. Microglia barrier formation has been suggested to prevent plaque growth, facilitate its compaction, and reduce plaque-induced toxicity to healthy neurons [63-65].

Figure 3:. Cellular and extracellular triggers of microglial activation during neurodegeneration.

Schematic displays the variety of molecular signals that can be involved in mediating FBR including activation of pathogen-associated pattern recognition receptors, such as toll-like receptors and scavenger receptors, to initiate inflammatory or phagocytic response [44,45]. The same receptors can also recognize damage-associated molecular patterns, that are released or exposed upon host danger, such as HMGB1 (released upon necrotic cell death) and fibrinogen (exposed upon disruption of extracellular matrix [44,45]. Another potent signal representing cellular damage is ATP, which is recognized by purinergic receptors expressed on microglia [45]. Identification of foreign particles can be mediated by the presence of “eat-me” or the lack of “don’t-eat-me signals”. These are pairs or macrophage-expressed receptors that bind their cognate ligands [42]. “Don’t-eat-me” signals can be mediated e.g. by the expression of CD47 on functional neurons and synapses, which by binding to SIRPα on myeloid cells triggers inhibition of (unwanted) phagocytosis. Conversely, opsonization of pathogen and foreign bodies by the complement system [43] can mediate strong “eat-me” signals via the activation of Fc receptors, such as FcγR3. A more recently characterized family of receptors are called triggering receptor expressed on myeloid cells (TREMs) which can recognize anionic lipids and ApoE found on plaques [41]. Given the chemically complex composition of amyloid plaques that can contain a variety of lipids, nucleic acids, carbohydrates, and misfolded proteins [47,48], it is likely that many of these receptors are simultaneously activated to drive a microglia response. In addition to chemical cues, mechanical cues, such as stiffness and surface roughness, are also potent triggers of FBR [46] and can directly affect the level of inflammatory response elicited [36]. Mechanical cues can be detected among others by specific mechanosensors expressed on microglia [46,76].