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Purines induce directed migration and rapid homing of microglia to injured pyramidal neurons in developing
Dana Kurpius1, Eric P Nolley, Michael E Dailey
1Department of Biological Sciences, The University of Iowa, Iowa City, Iowa 52242-1324, USA.
Abstract:
Traumatic CNS injury activates and mobilizes resident parenchymal microglia (MG), which rapidly accumulate near injured neurons where they transform into phagocytes. The mechanisms underlying this rapid 'homing' in situ are unknown. Using time-lapse confocal imaging in acutely excised neonatal hippocampal slices, we show that rapid accumulation of MG near somata of injured pyramidal neurons in the stratum pyramidale (SP) results from directed migration from tissue regions immediately adjacent to (<200 microm from) the SP. Time-lapse sequences also reveal a 'spreading activation wave' wherein MG situated progressively farther from the SP begin to migrate later and exhibit less directional migration toward the SP. Because purines have been implicated in MG activation and chemotaxis, we tested whether ATP/ADP released from injured pyramidal neurons might account for these patterns of MG behavior. Indeed, application of apyrase, which degrades extracellular ATP/ADP, inhibits MG motility and homing to injured neurons in the SP. Moreover, bath application of exogenous ATP/ADP disrupts MG homing by inducing directional migration toward the slice exterior and away from injured neurons. These results indicate that extracellular ATP/ADP is both necessary and sufficient to induce directional migration and rapid homing of neonatal MG to injured neurons in situ. Rapid, ATP/ADP-dependent MG homing may promote clearance of dead and dying cells and help limit secondary damage during the critical first few hours after neuronal injury.
Insights
Extracellular ATP/ADP drives microglia (MG) to injured neurons in the brain. This rapid, ATP/ADP-dependent homing of MG may help clear damaged cells and limit injury after CNS trauma.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Traumatic central nervous system (CNS) injury activates microglia (MG), the brain's resident immune cells.
- These activated MG rapidly accumulate near injured neurons, transforming into phagocytes to clear cellular debris.
- The precise mechanisms governing this rapid in situ MG homing remain largely unknown.
Purpose of the Study:
- To investigate the mechanisms underlying the rapid, directed migration of microglia to injured neurons following CNS trauma.
- To determine the role of extracellular purines, specifically ATP/ADP, in mediating microglial homing behavior in situ.
- To elucidate the potential contribution of ATP/ADP-dependent microglial responses to neuroprotection after injury.
Main Methods:
- Utilized time-lapse confocal imaging in acutely excised neonatal hippocampal slices to observe microglial behavior in real-time.
- Assessed microglial migration patterns and accumulation near injured pyramidal neurons in the stratum pyramidale.
- Manipulated extracellular purine levels using apyrase (to degrade ATP/ADP) and exogenous ATP/ADP application to study their effects on microglial homing.
Main Results:
- Demonstrated that microglia rapidly migrate directionally towards injured neurons from adjacent tissue regions (<200 microm).
- Observed a 'spreading activation wave' of microglial migration, with more distant cells migrating later and less directionally.
- Found that inhibiting extracellular ATP/ADP with apyrase significantly reduced microglial motility and homing to injured neurons.
- Showed that exogenous ATP/ADP application induced directional microglial migration away from injured neurons, disrupting normal homing.
Conclusions:
- Extracellular ATP/ADP released from injured neurons is both necessary and sufficient to induce rapid, directional microglial migration and homing in situ.
- This ATP/ADP-dependent microglial response plays a critical role in the initial hours following neuronal injury.
- Rapid microglial homing mediated by ATP/ADP likely contributes to the clearance of damaged cells and may limit secondary injury progression.
