Inflammation and neuroprotection in traumatic brain injury

Abstract

Importance: Traumatic brain injury (TBI) is a significant public health concern that affects individuals in all demographics. With increasing interest in the medical and public communities, understanding the inflammatory mechanisms that drive the pathologic and consequent cognitive outcomes can inform future research and clinical decisions for patients with TBI.

Objectives: To review known inflammatory mechanisms in TBI and to highlight clinical trials and neuroprotective therapeutic manipulations of pathologic and inflammatory mechanisms of TBI.

Evidence review: We searched articles in PubMed published between 1960 and August 1, 2014, using the following keywords: traumatic brain injury, sterile injury, inflammation, astrocytes, microglia, monocytes, macrophages, neutrophils, T cells, reactive oxygen species, alarmins, danger-associated molecular patterns, purinergic receptors, neuroprotection, and clinical trials. Previous clinical trials or therapeutic studies that involved manipulation of the discussed mechanisms were considered for inclusion. The final list of selected studies was assembled based on novelty and direct relevance to the primary focus of this review.

Findings: Traumatic brain injury is a diverse group of sterile injuries induced by primary and secondary mechanisms that give rise to cell death, inflammation, and neurologic dysfunction in patients of all demographics. Pathogenesis is driven by complex, interacting mechanisms that include reactive oxygen species, ion channel and gap junction signaling, purinergic receptor signaling, excitotoxic neurotransmitter signaling, perturbations in calcium homeostasis, and damage-associated molecular pattern molecules, among others. Central nervous system resident and peripherally derived inflammatory cells respond to TBI and can provide neuroprotection or participate in maladaptive secondary injury reactions. The exact contribution of inflammatory cells to a TBI lesion is dictated by their anatomical positioning as well as the local cues to which they are exposed.

Conclusions and relevance: The mechanisms that drive TBI lesion development as well as those that promote repair are exceedingly complex and often superimposed. Because pathogenic mechanisms can diversify over time or even differ based on the injury type, it is important that neuroprotective therapeutics be developed and administered with these variables in mind. Due to its complexity, TBI has proven particularly challenging to treat; however, a number of promising therapeutic approaches are now under pre-clinical development, and recent clinical trials have even yielded a few successes. Given the worldwide impact of TBI on the human population, it is imperative that research remains active in this area and that we continue to develop therapeutics to improve outcome in afflicted patients.

Conflict of interest statement

Disclosures: None reported.

Figures

Figure 1. Pathogenesis of Traumatic Brain Injury (TBI)

A, Comparison of brain anatomy in the meninges and superficial neocortex before and after focal mild TBI (mTBI). The dura mater contains numerous small vessels that are lined by thin, elongated meningeal macrophages. The subarachnoid space contains vessels, fibroblast like stromal cells, and cerebrospinal fluid (CSF). The glial limitans, composed of astrocytic foot processes, lies beneath the pia mater and forms a barrier between the CSF and underlying parenchyma. Mild focal brain injury mechanically compresses the meningeal space, compromising vascular integrity and inducing rapid necrosis of meningeal macrophages and structural cells. Leakage of fluid from meningeal blood vessels results in edema, and damaged cells within the meninges release reactive oxygen species (ROS) and adenosine triphosphate (ATP), initiating a sterile immune reaction. B and C, Maximum projections (5-μm wide) are shown in the xz plane of 2-photon z-stacks captured through the thinned skull of CX3CR1GFP/+ mice (original magnification ×20). B, A representative image of an uninjured mouse reveals the presence of meningeal macrophages (green) in the dura and ramified microglia (green) in the brain parenchyma beneath the glial limitans (white dotted line). C, Thirty minutes after focal mTBI, meningeal macrophages die and microglia relocate to the injured glial limitans (arrowheads). Skull bone is shown in blue. D and E, Histopathologic analysis of the superficial neocortex by confocal microscopy 8 hours after mTBI (original magnification ×20). D, An uninjured brain is shown for comparison. Dead cells were labeled transcranially with propidium iodide. Cell nuclei are blue. E, A large lesion consisting of numerous dead cells (red) (arrowhead). See Videos 1 and 2. UPD indicates uridine diphosphate.

Figure 2. Inflammatory Reaction to Traumatic Brain Injury

A–I, The 25-μm xy maximum projections from CX3CR1GFP/+ (A, B, and D–I) or LysMGFP/+ (C) mice were captured by 2-photon microscopy through a thinned skull. A, Meningeal macrophages (green) are thin, elongated cells that reside along the dural blood vessels in the uninjured brain. B, After focal mild traumatic brain injury (mTBI), meningeal macrophages undergo necrosis within 30 minutes and disappear from the field of view. C, Myelomonocytic cells (green) invade the damaged meninges within an hour of brain injury. D and G, In the uninjured brain, microglia (green) have small cell bodies and are highly ramified. Focal brain injury induces the rapid transformation of microglia into at least 2 distinct morphologic patterns. E and H, Honeycomb microglia extend processes that circumscribe the borders between individual astrocytes in the glial limitans. F and I, Phagocytic jellyfish microglia are generated in response to cell death and form a film across the damaged glial limitans. High-magnification views in panels G through I are denoted with white boxes in panels D through F (original magnification ×20). See Videos 1 and 2.