Head injuries can trigger serious, potentially life threatening cellular injury responses in the meninges and underlying brain parenchyma. Innate immune sentinels such microglia, macrophages, and neutrophils directly participate in these injury responses, but little is known about how these cells respond in their local milieu. To gain novel mechanistic insights into acute brain injury responses, we developed a model of meningeal compression in which the meningeal space is collapsed to varying degrees. Following injury we monitored the innate immune injury response in real time for up to 24 hours using intravital two photon laser scanning microscopy (TPLSM) in combination with a newly developed technique that allows transcranial application of fluorescent dyes and other small molecules directly through the skull bone. We observed that following compression injury meningeal macrophages undergo rapid necrosis, releasing their contents into the subarachnoid space. This mediates a breach in the glial limitans, which triggers transformation of underlying parenchymal microglia into massive phagocytic machines with a jellyfish-like morphology. These microglia migrate to the compromised glial limitans and appear to form a phagocytic barrier between the meninges and brain parenchyma. Interestingly, phagocytic microglia were always associated with areas of barrier compromise despite the continued survival of astrocytes comprising the glial limitans. The microglial response to meningeal compression was immediate and followed shortly thereafter by swarms of neutrophils that invaded the injury site. Neutrophils remained exclusively in the meninges and likely participated in cleaning up necrotic cells. Our imaging studies provide a detailed understanding of how the brain responds in real time to an acute injury and establishes a framework for testing therapeutics designed to resolve the injury response and promote repair.
Last updated December 23, 2013