Tight squeeze, slow burn: inflammation and the aetiology of cervical myelopathy.

A great deal of progress has been made over the past decade in understanding the role of secondary injury in the progression of brain and spinal cord injury, and the innate immune response has emerged as an important potential therapeutic target (e.g. Beattie, 2004; Donnelly and Popovich, 2008). The microglial response to CNS damage and subsequent invasion of the lesion by peripheral macrophages are associated with the production of proinflammatory cytokines and related immune effector molecules that can induce cell death through necrosis and apoptosis both in neurons and oligodendrocytes. Brain and spinal cord injury can initiate a long-lasting cascade of oligodendrocyte death that may lead to chronic demyelination, adding to the dysfunction (e.g. Crowe et al., 1997; Beattie et al., 2002), and this cascade is driven at least in part through the actions of immune mediators including pro-inflammatory cytokines (Donnelly and Popovich, 2008). Thus, neuroinflammation has been identified as a target for pharmacological therapies, with some evidence of success in animal models of acute spinal cord injury. For example, the anti-inflammatory antibiotic minocycline has been shown to reduce oligodendrocyte apoptosis and spare function in acute cervical spinal cord injury (Stirling et al., 2004). Neuroinflammation has also been identified as a contributor to cell death in ischaemic stroke and chronic neurodegenerative disorders; and these findings point to the potential commonality of mechanisms underlying cell damage and death in both acute neural injury and slow-developing pathologies like those seen in Alzheimer’s disease and amyotrophic lateral sclerosis. Now, in this issue of Brain, Yu et al. (2011) provide evidence that cervical spondylotic myelopathy, a slow progressive compression injury to the cord and arguably the most prevalent form of spinal cord injury, also involves innate immune responses that contribute to neuronal and oligodendrocyte death, similar to that seen in acute spinal cord injury. Further, they demonstrate that the immunological injury is mediated at least in part by Fas (also known as CD95 or APO-1 receptors) and Fas ligand, components of the immune response known to induce apoptosis. These new results focus attention on the clinical importance of cervical spondylotic myelopathy, and provide a rationale for targeting cell death by pharmacological neuroprotection in addition to treatment by the usual route of surgical decompression (reviewed in Fehlings and Skaf, 1998). Cervical spondylotic myelopathy is characterized by progressive stenosis of the cervical canal and compression of the spinal cord due to degenerative changes in the spine, including degeneration of the intervertebral discs, joints and ligaments. Symptoms usually begin after the age of 50 years with slowly progressive neck stiffness, numbness and myelopathy. Human pathological findings include cord flattening, loss of anterior horn cells, demyelination and axonal degeneration (Fehlings and Skaf, 1998). Functional loss has been thought to be due to mechanical disruption of the cord, especially with hyperextension injuries, as well as compressioninduced ischaemia. Fas/CD95 is a receptor that is a member of the tumour necrosis factor (TNF)receptor superfamily; it initiates cell death via Fas ligand binding-dependent attraction of Fas-associated proteincontaining death domain (FADD) to the CD95 death domain to drive caspase-mediated apoptosis (reviewed in Letellier et al., 2010). In addition to a role in peripheral inflammation, a number of previous studies have implicated this signalling pathway in cell death following spinal cord injury (Casha et al., 2004; Demjen et al., 2004; Ackery et al., 2006). Fas is present on neurons and oligodendrocytes, and may be up-regulated after injury (Ackery et al., 2006), as has been reported for other members of the TNFreceptor superfamily (e.g. the p75 neurotrophin receptor; Beattie et al., 2002; and TNF receptor 1). Further, Fas ligand may initiate pro-inflammatory cytokine production by binding to Fas on microglia or astrocytes, which could also lead to cell death in the lesion zone. Yu et al. (2011) found evidence for both Fas ligand and Fas in human cervical spinal cords from patients with significant cervical spondylotic myelopathy that also exhibited the classical pathological signs of neuronal loss and axon degeneration. They also identified ongoing apoptosis of neurons, oligodendrocytes and microglial cells, and these cells often also expressed Fas ligand. Given the similarity of these findings to those of acute spinal cord injury, the authors hypothesize that blockade of Fas ligand might also be a therapeutic strategy in cervical spondylotic myelopathy. While this might seem obvious at first, there are many potential differences in the innate immune response to acute contusion injuries versus the kind of chronic, slow compression seen in cervical spondylotic myelopathy. In order to test the hypothesis, they took advantage of a hyperostotic mouse mutant that Brain 2011: 134; 1259–1263 | 1259