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

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          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.

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          Most cited references48

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          Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

          Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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            The P2Y12 receptor regulates microglial activation by extracellular nucleotides.

            Microglia are primary immune sentinels of the CNS. Following injury, these cells migrate or extend processes toward sites of tissue damage. CNS injury is accompanied by release of nucleotides, serving as signals for microglial activation or chemotaxis. Microglia express several purinoceptors, including a G(i)-coupled subtype that has been implicated in ATP- and ADP-mediated migration in vitro. Here we show that microglia from mice lacking G(i)-coupled P2Y(12) receptors exhibit normal baseline motility but are unable to polarize, migrate or extend processes toward nucleotides in vitro or in vivo. Microglia in P2ry(12)(-/-) mice show significantly diminished directional branch extension toward sites of cortical damage in the living mouse. Moreover, P2Y(12) expression is robust in the 'resting' state, but dramatically reduced after microglial activation. These results imply that P2Y(12) is a primary site at which nucleotides act to induce microglial chemotaxis at early stages of the response to local CNS injury.
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              Control of microglial neurotoxicity by the fractalkine receptor.

              Microglia, the resident inflammatory cells of the CNS, are the only CNS cells that express the fractalkine receptor (CX3CR1). Using three different in vivo models, we show that CX3CR1 deficiency dysregulates microglial responses, resulting in neurotoxicity. Following peripheral lipopolysaccharide injections, Cx3cr1-/- mice showed cell-autonomous microglial neurotoxicity. In a toxic model of Parkinson disease and a transgenic model of amyotrophic lateral sclerosis, Cx3cr1-/- mice showed more extensive neuronal cell loss than Cx3cr1+ littermate controls. Augmenting CX3CR1 signaling may protect against microglial neurotoxicity, whereas CNS penetration by pharmaceutical CX3CR1 antagonists could increase neuronal vulnerability.
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                Author and article information

                Journal
                Brain
                brainj
                brain
                Brain
                Oxford University Press
                0006-8950
                1460-2156
                February 2009
                20 June 2008
                20 June 2008
                : 132
                : 2
                : 288-295
                Affiliations
                1 Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn, Bonn, Germany 2 Department of Neurosurgery, Medical University Vienna, Vienna, Austria 3 Department of Neurosurgery, University of Göttingen, Göttingen, Germany 4 Department of Veterinary Medicine and Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK
                Author notes
                Correspondence to: Harald Neumann, Neural Regeneration, Institute of Reconstructive Neurobiology, University Bonn and Hertie-Foundation, Sigmund-Freud-Str. 25, 53127 Bonn, Germany E-mail: hneuman1@ 123456uni-bonn.de
                Article
                awn109
                10.1093/brain/awn109
                2640215
                18567623
                3a2a2c41-1d1a-43d2-8e59-492eea9b6274
                © 2008 The Author(s)

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 March 2008
                : 8 May 2008
                : 9 May 2008
                Categories
                Review Article

                Neurosciences
                neurodegeneration,phagocytosis,multiple sclerosis, alzheimer disease,regeneration,neuroinflammation,microglia

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