Spinal cord injury (SCI) is a devastating clinical condition often resulting in paralysis below the level of injury and the development of secondary complications such as chronic pain and autonomic dysreflexia [
1]. Broadly speaking, the primary injury is mediated by an initial traumatic event to the cord resulting in neuronal and glial injury/death and disruption of the blood-spinal cord barrier at the epicenter, which is almost immediately followed by a secondary wave of neuronal and gliatoxic sequelae including a rapid increase in glutamate, immunoregulatory cytokines such as tumor necrosis factor (TNF), toxic lipid metabolites, and, over time, the infiltration of peripheral blood leukocytes such as neutrophils, macrophages, and T-cells [
2]. The immune system plays a dual role in both pathological destruction of neuronal tissue as well as in tissue repair and to some extent functional recovery [
3]-[
11]. Understanding the dichotomy between tissue destruction and tissue repair is essential for the development of effective therapies for SCI and other neurodegenerative disorders.
TNF is a pleiotropic cytokine important in the regulation of numerous physiological and pathological processes such as inflammation, autoimmunity, neurodegeneration, neuroprotection, demyelination, and remyelination [
9],[
12]-[
18]. There are two active forms of TNF, soluble-TNF (solTNF) and transmembrane-TNF (tmTNF), whose biological responses are primarily mediated by two distinct receptors, TNFR1 and TNFR2, respectively. TNFR1 has a death domain and signaling through this receptor has been implicated in both neuronal and oligodendrocyte death [
9],[
15],[
17],[
19], whereas signaling through TNFR2 has been implicated in neuroprotection and remyelination [
9],[
20],[
21]. Expression studies demonstrate that TNF is upregulated in the spinal cord within minutes to hours following injury and coincides with elevated glutamate, suggesting that injury-induced cytotoxicity may be mediated through additive or synergistic interactions between these and other soluble factors [
2],[
10]. Studies using genetically engineered mice lacking either TNFR1 or TNFR2 show that TNF and its receptors indeed play a role in functional recovery and pathology following SCI [
22]. While the behavioral data are difficult to interpret because the Basso, Beattie, and Bresnahan test was applied to evaluate changes in locomotor function in mice; the histological data are clear, deleting TNFR1 significantly reduces tissue damage [
22]. In support of these studies, mice lacking TNFR1 (TNFR1
-/-), the receptor preferentially activated by solTNF, are protected from experimental allergic encephalomyelitis (EAE) - a mouse model of multiple sclerosis - and have reduced pathology and normal remyelination [
21],[
23],[
24]. Conversely, mice lacking TNF (TNF
-/-) or TNFR2 (TNFR2
-/-), the primary receptor for tmTNF, have worse functional outcome and do not remyelinate when exposed to EAE. Studies using genetically modified mice expressing only tmTNF show that this form of the cytokine, signaling through TNFR2, is sufficient to suppress the induction and progression of EAE [
25]. Finally, we and others recently determined that systemic delivery of a selective inhibitor of solTNF, XPro1595, which binds solTNF forming inactive heterodimers [
26], significantly improves functional recovery, reduces axonal damage, and promotes remyelination. In contrast, inhibition of solTNF and tmTNF with the non-specific TNF inhibitor, etanercept (decoy TNFR2 which blocks solTNF, tmTNF, and lymphotoxin [
27]), proved neither therapeutic nor neuroprotective in EAE [
9],[
20].
Based upon these and other data, we sought to investigate whether a pharmacological inhibition of solTNF or total TNF was therapeutic following SCI. Our results suggest that selectively targeting solTNF directly in the cord may be a new therapeutic avenue for this clinically devastating condition.