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Regulation of microglial expression of integrins by poly(ADP-ribose) polymerase-1
O Ullrich1, A Diestel, I Y Eyüpoglu
1Department of Cell- and Neurobiology, Institute of Anatomy. Medical Faculty (Charité), Humboldt-University Berlin, Schumannstrasse 20/21, 10098 Berlin, Germany. oliver.ullrich@charite.de
Abstract:
Excitotoxic brain lesions initially result in the primary destruction of brain parenchyma, after which microglial cells migrate towards the sites of injury. At these sites, the cells produce large quantities of oxygen radicals and cause secondary damage that accounts for most of the loss of brain function. Here we show that this microglial migration is strongly controlled in living brain tissue by expression of the integrin CD11a, regulated by the nuclear enzyme poly(ADP-ribose) polymerase-1 (PARP-1) through the formation of a nuclear PARP-NF-kappaB-protein complex. Downregulation of PARP or CD11a by transfection with antisense DNA abrogated microglial migration almost completely and prevented neurons from secondary damage.
Insights
Microglial cell migration to brain injury sites, causing secondary damage, is controlled by integrin CD11a. Targeting poly(ADP-ribose) polymerase-1 (PARP-1) and CD11a with antisense DNA prevents this migration and neuronal damage.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Excitotoxic brain lesions cause primary neuronal destruction.
- Microglial cells migrate to injury sites, producing oxygen radicals and causing secondary damage.
- This secondary damage significantly contributes to functional brain loss.
Purpose of the Study:
- To investigate the molecular mechanisms controlling microglial cell migration following excitotoxic brain injury.
- To identify key regulators of microglial migration and subsequent secondary brain damage.
Main Methods:
- Studied microglial migration in living brain tissue.
- Investigated the role of integrin CD11a and poly(ADP-ribose) polymerase-1 (PARP-1).
- Utilized antisense DNA transfection to downregulate PARP-1 and CD11a expression.
Main Results:
- Microglial migration is controlled by integrin CD11a expression.
- PARP-1 regulates CD11a expression via a nuclear PARP-NF-kappaB-protein complex.
- Downregulation of PARP-1 or CD11a abrogated microglial migration.
- Prevented secondary neuronal damage.
Conclusions:
- Integrin CD11a is a critical regulator of microglial cell migration to excitotoxic brain lesions.
- The PARP-1 pathway plays a key role in controlling CD11a expression and subsequent microglial migration.
- Targeting PARP-1 or CD11a offers a potential therapeutic strategy to prevent secondary brain damage.