Anterograde Transport of Tumor Necrosis Factor-α in the Intact and Injured Rat Sciatic Nerve

Abstract

Tumor necrosis factor-alpha (TNF) appears as a key player at both central and peripheral terminals in early degenerative pathology and pain behavior after peripheral nerve injury. Recent studies suggest that TNF may be axonally transported and thereby contribute to these central and peripheral actions. To characterize this transport, we used a double ligation (DL) procedure that distinguishes between anterograde and retrograde flow to visualize the axonal transport of endogenous TNF compared with the neurotrophin nerve growth factor (NGF) and to the neuropeptide calcitonin gene-related peptide (CGRP). In the intact nerve, TNF and CGRP immunoreactivity predominantly accumulated proximal to the DL (anterograde transport), whereas NGF displayed exclusive retrograde transport. At 20 hr after chronic constrictive injury (CCI), the anterograde transport of TNF and CGRP to the nerve injury site was dramatically increased. The results were corroborated by the analysis of axonal transport of exogenously applied 125I-TNF and 125I-NGF. After intraneural injection, 125I-TNF accumulated proximally to a DL, suggesting anterograde transport. In the unligated nerve, 125I-TNF was specifically transported anterogradely to the innervated muscle but not to skin. After CCI, 125I-TNF accumulated proximally to the peripheral nerve injury site, and endogenous TNF was exclusively increased in medium-sized and large dorsal root ganglion (DRG) neurons, suggesting that DRG neurons are a major contributing source of increased TNF traffic in the injured sciatic nerve. Our results suggest that anterograde transport of TNF plays a major role in the early neuronal response to peripheral nerve injury at sites distal to the cell body.

Antinociceptive effects of tumor necrosis factor α neutralization in a rat model of antigen‐induced arthritis: Evidence of a neuronal target

“…Several reports have described the expression of both TNFRI and TNFRII in rat DRG neurons (16)(17)(18)(19)(20)(21), but other studies identified only TNFRI in neurons, while localizing TNFRII in nonneuronal cells in the DRG (22,23). All of these findings support the hypothesis that treatment with etanercept or infliximab not only influences the inflammation process, but exerts antinociceptive effects by reducing direct pronociceptive actions of TNF␣ on nerve fibers.…”

Enhanced Transmission at a Spinal Synapse TriggeredIn Vivoby an Injury Signal Independent of Altered Synaptic Activity

“…For example, the pro-inflammatory cytokine tumor necrosis factor ␣ (TNF␣) increases quickly at the site of peripheral nerve injury (Taskinen et al, 2000) and can increase glutamatergic synaptic strength (Bains and Oliet, 2007). However, TNF␣ does not qualify given evidence that it is not carried by retrograde transport to the DRG in injured nerves (Schafers et al, 2002) and is not restricted to primary afferents that are injured (Schafers et al, 2003). In contrast, the neurotrophin BDNF is a viable candidate by our criteria.…”

Increased Sensitivity of Injured and Adjacent Uninjured Rat Primary Sensory Neurons to Exogenous Tumor Necrosis Factor-α after Spinal Nerve Ligation

“…Exogenous TNF may stimulate injured DRG by triggering one or more cascades, e.g., stimulating production of neurotrophins (Lindholm et al, 1987;Yoshida and Gage, 1992;Hattori et al, 1996,), which in turn may trigger sensitizing neuropeptides or further enhance DRG neuronal responses to capsaicin (Nicol et al, 1997). After sciatic nerve lesions, proinflammatory cytokines including TNF (Schäfers et al, 2002) and IL-6 (Murphy et al, 1995) are upregulated in lumbar DRG. These display synergistic algesic effects with TNF (Schäfers et al, 2001;Sweitzer et al, 2001).…”

“…Proinflammatory cytokines such as tumor necrosis factor-␣ (TNF) that are released after injury have been proposed as initiators (Wagner and Myers, 1996;Sommer and Schäfers, 1998;Sorkin and Doom, 2000). After peripheral nerve injury, DRG neurons robustly increase their expression of TNF (Schäfers et al, 2002). Exogenous TNF applied to intact or compression-injured DRG induces sustained mechanical allodynia (Homma et al, 2002).…”