Debris clearance by microglia: an essential link between degeneration and regeneration

Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn and Hertie-Foundation, Bonn, Germany.
Brain (Impact Factor: 10.23). 07/2008; 132(Pt 2):288-95. DOI: 10.1093/brain/awn109
Source: PubMed

ABSTRACT Microglia are cells of myeloid origin that populate the CNS during early development and form the brain's innate immune cell type. They perform homoeostatic activity in the normal CNS, a function associated with high motility of their ramified processes and their constant phagocytic clearance of cell debris. This debris clearance role is amplified in CNS injury, where there is frank loss of tissue and recruitment of microglia to the injured area. Recent evidence suggests that this phagocytic clearance following injury is more than simply tidying up, but instead plays a fundamental role in facilitating the reorganization of neuronal circuits and triggering repair. Insufficient clearance by microglia, prevalent in several neurodegenerative diseases and declining with ageing, is associated with an inadequate regenerative response. Thus, understanding the mechanism and functional significance of microglial-mediated clearance of tissue debris following injury may open up exciting new therapeutic avenues.

Download full-text


Available from: Mark R Kotter, May 07, 2014
1 Follower
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Microglial cells are the resident macrophages of the central nervous system (CNS). Their function is essential for neuronal tissue homeostasis. After inflammatory stimuli, microglial cells become activated changing from a resting and highly ramified cell shape to an amoeboid-like morphology. These morphological changes are associated with the release of pro-inflammatory cytokines and glutamate, as well as with high phagocytic activity. The acquisition of such phenotype has been associated with activation of cytoplasmic tyrosine kinases, including those of the Src family (SFKs). In this study, using both in vivo and in vitro inflammation models coupled to FRET-based time-lapse microscopy, lentiviruses-mediated shRNA delivery and genetic gain-of-function experiments, we demonstrate that among SFKs c-Src function is necessary and sufficient for triggering microglia pro-inflammatory signature, glutamate release, microglia-induced neuronal loss and phagocytosis. c-Src inhibition in retinal neuroinflammation experimental paradigms consisting of intravitreal injection of LPS or ischemia-reperfusion injury significantly reduced microglia activation changing their morphology to a more resting phenotype and prevented neuronal apoptosis. Our data demonstrate an essential role for c-Src in microglial cell activation.
    Glia 03/2015; 63(3). DOI:10.1002/glia.22767 · 6.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Peripheral immune cells are critical to the pathogenesis of neurodegenerative diseases including multiple sclerosis (MS) (Hendriks et al., 2005; Kasper and Shoemaker, 2010). However, the precise sequence of tissue events during the early asymptomatic induction phase of experimental autoimmune encephalomyelitis (EAE) pathogenesis remains poorly defined. Due to the spatial-temporal constrains of traditional methods used to study this disease, most studies had been performed in the spine during peak clinical disease; thus the debate continues as to whether tissue changes such as vessel disruption represents a cause or a byproduct of EAE pathophysiology in the cortex. Here, we provide dynamic, high-resolution information on the evolving structural and cellular processes within the grey matter of the mouse cortex during the first 12 asymptomatic days of EAE induction. We observed that transient focal vessel disruptions precede microglia activation, followed by infiltration of and directed interaction between circulating dendritic cells and T cells. Histamine antagonist minimizes but not completely ameliorates blood vessel leak. Histamine H1 receptor blockade prevents early microglia function, resulting in subsequent reduction in immune cell accumulation, disease incidence and clinical severity. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 02/2015; 111. DOI:10.1016/j.expneurol.2015.02.018 · 4.62 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Implantable 'structural bridges' based on nanofabricated polymer scaffolds have great promise to aid spinal cord regeneration. Their development (optimal formulations, surface functionalizations, safety, topographical influences and degradation profiles) is heavily reliant on live animal injury models. These have several disadvantages including invasive surgical procedures, ethical issues, high animal usage, technical complexity and expense. In vitro 3-D organotypic slice arrays could offer a solution to overcome these challenges, but their utility for nanomaterials testing is undetermined. We have developed an in vitro model of spinal cord injury that replicates stereotypical cellular responses to neurological injury in vivo, viz. reactive gliosis, microglial infiltration and limited nerve fibre outgrowth. We describe a facile method to safely incorporate aligned, poly-lactic acid nanofibre meshes (±poly-lysine + laminin coating) within injury sites using a lightweight construct. Patterns of nanotopography induced outgrowth/alignment of astrocytes and neurons in the in vitro model were strikingly similar to that induced by comparable materials in related studies in vivo. This highlights the value of our model in providing biologically-relevant readouts of the regeneration-promoting capacity of synthetic bridges within the complex environment of spinal cord lesions. Our approach can serve as a prototype to develop versatile bio-screening systems to identify materials/combinatorial strategies for regenerative medicine, whilst reducing live animal experimentation.
    Biomaterials 01/2014; DOI:10.1016/j.biomaterials.2014.01.022 · 8.31 Impact Factor