ATP mediates rapid microglial response to local brain injury in vivo

Abstract

Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis

“…58,59 Injury-triggered extracellular ATP also affects microglial response following brain injury. 60,61 We have identified that injury-triggered lysosome exocytosis causes secretion of acid sphingomyelinase (ASM), which is needed for cell membrane repair. 16 ASM secretion by glial cells is also triggered by ATP, which in turn regulates secretion of inflammatory cytokines.…”

Neuroinflammation: Ways in Which the Immune System Affects the Brain

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Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Resident microglia in the healthy brain display a ''resting state" appearing in a downgraded phenotype, with highly ramified morphology and a low expression of membrane receptors that serve 0091 immunological functions [123]; even in this resting state microglia are highly active as shown by the high motility of their processes and protrusions observed by two-photon imaging analysis of brain in vivo ( [53,173]). Microglia are the first cell type that sense any form of disturbance of the brain and rapidly activate through a well-characterized and graded response; the inner cytoskeleton changes and the cell body becomes enlarged, bearing shorter and thicker cytoplasmic processes ( [174,218]).…”