ReviewInflammation and its role in neuroprotection, axonal regeneration and functional recovery after spinal cord injury
Introduction
Central nervous system (CNS) trauma, either in the form of traumatic brain injury (TBI) or spinal cord injury (SCI), causes marked neuropathology and limited functional recovery. While mechanical trauma rapidly kills neurons and glia, an insidious and delayed secondary pathology follows. The latter may be amenable to therapy and is characterized by neuronal and glial apoptosis, increased blood–CNS barrier permeability and a complex and poorly understood neuroinflammatory response that can persist for months or years after the initial trauma (Fleming et al., 2006, Norenberg et al., 2004, Profyris et al., 2004).
The role of neuroinflammation is controversial. Both beneficial and detrimental effects have been ascribed to microglia/macrophages (CNS macrophages), lymphocytes, antibodies and cytokines. The goal of this review is to address the complexities and controversies of this response with an emphasis on SCI. In addition, we will discuss pre-clinical and clinical therapies that target neuroinflammation, addressing those that suppress or enhance the immune response.
Section snippets
Traumatically injured brain and spinal cord elicit distinct neuroinflammatory reactions
Although inflammation is a ubiquitous consequence of CNS trauma, the temporal sequence, composition and magnitude of this response in brain are distinct from spinal cord. Schnell and colleagues proved this point by comparing the inflammatory responses elicited by identical injuries delivered to mouse brain and spinal cord (Schnell et al., 1999a). Following a parasagittal incision to the cortex or a similar incision to the dorsal spinal cord, marked differences in cellular inflammation were
Species and strain-dependent differences in the neuroinflammatory response to spinal cord injury
Neuroinflammatory responses to SCI vary between species and strains of a given species. These differences are unlikely to be due to variable degrees of primary trauma between small and large animals. Spinal contusion and compression injury cause acute central hemorrhagic necrosis in all mammals and are accompanied by prominent glial activation and leukocyte infiltration (see Fig. 1B) (Fleming et al., 2006, Hausmann, 2003, Popovich et al., 1997, Sroga et al., 2003). However, the onset, duration
Changes in microvascular permeability after CNS injury: relationship to intraparenchymal inflammation
A prelude to the inflammatory response elicited by CNS trauma, and perhaps a consequence of this response at later times post-injury, is an increase in blood–brain barrier permeability (see Fig. 1E) (Habgood et al., 2007, Mautes et al., 2000, Noble and Wrathall, 1989, Popovich et al., 1996a, Popovich et al., 1997, Schnell et al., 1999a, Whetstone et al., 2003). Using a rat model of spinal contusion injury, Noble and Wrathall initially described injury-induced changes in permeability to
Neutrophils and macrophages
Via the release of cytokines, free radicals, eicosanoids and proteases, activated neutrophils and macrophages can cause neuronal and glial toxicity (see Fig. 1A) (Bao and Liu, 2002, Brady et al., 2006, Chandler et al., 1995, Chao et al., 1992, Liu et al., 2006, Merrill et al., 1993, Newman et al., 2001, Shamash et al., 2002). This toxic potential has been demonstrated repeatedly in various models of SCI. Protocols to deplete or neutralize neutrophils and macrophages or inhibit their functions,
Neutrophils and macrophages
Given their primary function as bactericidal cells, it is doubtful that neutrophils exert neuroprotection in the CNS. This is not true for CNS macrophages. Despite being adept killers of neurons and glia, microglia may be intrinsically neuroprotective; they regularly survey the CNS and provide trophic support to neurons and glia (Banati and Graeber, 1994, Kreutzberg, 1996, Nimmerjahn et al., 2005). Indeed, it makes little sense to have evolved a homogeneously distributed network of cells
Immunomodulatory and cell-specific therapies for SCI
Methylprednisolone (MP), a potent immunosuppressive glucocorticoid, can successfully suppress various indices of neuroinflammation in experimental SCI models (Bartholdi and Schwab, 1995, Fu and Saporta, 2005, Xu et al., 1998, Xu et al., 2001). Although MP is the current standard of care for human SCI, the effectiveness and safety of this drug have recently been questioned (Coleman et al., 2000, Hurlbert, 2000, Qian et al., 2000). Because immune responses in the CNS can have dual effects, global
Conclusions
Despite extensive experimental data implicating inflammation as a pathogenic component of SCI, inflammation also appears to be pivotal for tissue repair. A challenge for researchers is to learn how to control cross-talk between the nervous and immune systems to minimize delayed neurodegeneration while promoting axonal plasticity and regeneration. Moreover, a greater appreciation for how SCI influences leukocyte development, activation and mobilization within and from peripheral lymphoid tissues
Acknowledgment
The work was funded by NIH grant # 746703 (National Institute for Neurological Disorders and Stroke; NINDS).
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