Elsevier

Experimental Neurology

Volume 258, August 2014, Pages 112-120
Experimental Neurology

Review
Is neuroinflammation in the injured spinal cord different than in the brain? Examining intrinsic differences between the brain and spinal cord

https://doi.org/10.1016/j.expneurol.2014.04.007Get rights and content

Abstract

The field of neuroimmunology is rapidly advancing. There is a growing appreciation for heterogeneity, both in inflammatory composition and region-specific inflammatory responses. This understanding underscores the importance of developing targeted immunomodulatory therapies for treating neurological disorders. Concerning neurotrauma, there is a dearth of publications directly comparing inflammatory responses in the brain and spinal cord after injury. The question therefore remains as to whether inflammatory cells responding to spinal cord vs. brain injury adopt similar functions and are therefore amenable to common therapies. In this review, we address this question while revisiting and modernizing the conclusions from publications that have directly compared inflammation across brain and spinal cord injuries. By examining molecular differences, anatomical variations, and inflammatory cell phenotypes between the injured brain and spinal cord, we provide insight into how neuroinflammation relates to neurotrauma and into fundamental differences between the brain and spinal cord.

Introduction

When tasked with answering the question: “does neuroinflammation differ between the injured spinal cord and injured brain”, one is immediately limited by the small number of studies that have directly compared inflammation after traumatic spinal cord and brain injury (SCI and TBI respectively). In fact, to the best of our knowledge there are only two papers that have done so (Batchelor et al., 2008, Schnell et al., 1999a). The general conclusions from those papers are that the magnitude of the inflammatory response is greater in the injured spinal cord than the brain.

Although the magnitude of the inflammatory response to SCI and TBI may be different, a number of questions with important implications for therapeutic development remain. For instance, are the inflammatory responses different enough that customized therapies for spinal cord or brain injury could not be used interchangeably? What cellular or mechanistic differences contribute to these different inflammatory responses and do they inform us about therapeutic efficacies between the two types of injuries? Although the magnitude of the inflammatory response may differ between the two injury types, does the composition of inflammatory cells and mediators vary? Could the inflammatory response play a more beneficial role in one type of injury than the other? Do inflammatory cells adopt the same functions in the injured brain and spinal cord?

Throughout the course of this review, we will attempt to answer these questions. First, we will revisit the findings of Schnell et al. (1999a) and Batchelor et al. (2008) and discuss them in the current and evolving field of neuroinflammation. Next we will compare and contrast anatomical and molecular components of the brain and spinal cord that influence trauma-induced inflammation. Lastly, we will discuss the potential functions of inflammatory cells in the injured brain and spinal cord with regard to cross-injury therapeutic efficacy and application. Through this examination we hope to provide insight into neuroinflammation as it relates to neurotrauma and gain insight into fundamental differences between the brain and spinal cord.

Section snippets

What we know from direct comparisons between SCI and TBI

When comparing and contrasting inflammatory responses to SCI and TBI, methodological differences in injury severity, injury type, animal strains and species, and analytical techniques potentially confound any differences evident across different studies. For instance with regard to SCI, the neutrophil response is protracted in mice compared to rats (Dusart and Schwab, 1994, Kigerl et al., 2006, Means and Anderson, 1983, Taoka et al., 1997); different strains of mice and rats have different

BBB vs. BSCB

The mechanisms contributing to the inflammatory disparity after SCI vs. TBI are not well understood but may result from inherent differences in blood–CNS barriers (Bartels et al., 2009, Ji et al., 2008). BBB integrity is related to immune cell infiltration into the diseased brain (Scott et al., 2004); when integrity is compromised, immune cell infiltration is increased (Zhang and Popovich, 2011). Similar to the BBB, which maintains the homeostasis between brain parenchyma and peripheral

Microglia/macrophages

While the findings of Schnell et al. (1999a) and Batchelor et al. (2008) demonstrate that the magnitude of the macrophage response is larger after SCI vs. TBI, the role these cells may be playing in repair or pathology after the two types of injury remains unknown. Since the publications of those influential papers, we have learned that macrophages with dual properties to promote regeneration and cause tissue pathology can be activated in the CNS (Gensel et al., 2009) and that heterogeneous

Neutrophils

In both SCI and TBI models, neutrophils accumulate at the injury site within hours and peak by 2 to 3 dpi. As reported above however, the magnitude of the neutrophil response is larger in the spinal cord vs. the brain (Schnell et al., 1999a; Fig. 1). The disparity in responses between CNS compartments may be attributable to the higher expression levels of cell adhesion molecules (CAMs) in the injured spinal cord compared to the injured brain (Schnell et al., 1999a). CAMs and chemokines mediate

Adaptive immune responses: B and T cells

The adaptive immune response to CNS injury is less prominent than the innate response. Although T and B cells are detectible acutely and chronically after brain and spinal cord injury, compared to innate immune cells, the numbers of T and B cells are relatively low. Roughly 10–20 fold fewer T cells respond to CNS trauma compared to macrophages (Beck et al., 2010, Jin et al., 2012). Although 2–3 × more cells respond to SCI vs. TBI when compared directly, the time course of T and B cell activation

Conclusions and comments

There are two studies that have directly compared neuroinflammation following identical traumas in the brain and spinal cord (Batchelor et al., 2008, Schnell et al., 1999a). The conclusions from these studies are that the inflammatory responses, facilitated through blood–CNS barrier compromise and consisting of macrophage/microglia activation, neutrophil recruitment, and accumulation of B and T cells are greater in the spinal cord compared to the brain. Differences between the brain and spinal

Acknowledgments

This work is supported by a Kentucky Spinal Cord and Head Injury Research Trust (KSCHIRT) Fellowship (Bei Zhang), The University of Kentucky, and The Craig H. Neilsen Foundation. In addition, we would like to thank the editors and reviewer for their helpful suggestions.

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