Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Abstract

The temporal relationship between severity of peripheral axonal injury and T lymphocyte trafficking to the neuronal cell bodies of origin in the brain has been unclear. We sought to test the hypothesis that greater neuronal death induced by disparate forms of peripheral nerve injury would result in differential patterns of T cell infiltration and duration at the cell bodies of origin in the brain and that these measures would correlate with the magnitude of neuronal death over time and cumulative neuronal loss. To test this hypothesis, we compared the time course of CD3 + T cell infiltration and neuronal death (assessed by CD11b + perineuronal microglial phagocytic clusters) following axonal crush versus axonal resection injuries, two extreme variations of facial nerve axotomy that result in mild versus severe neuronal loss, respectively, in the facial motor nucleus. We also quantified the number of facial motor neurons present at 49 days post-injury to determine whether differences in the levels of neuronal death between nerve crush and resection correlated with differences in cumulative neuronal loss. Between 1-7 days post-injury when levels of neuronal death were minimal, we found that the rate of accumulation and magnitude of the T cell response was similar following nerve crush and resection. Differences in the T cell response were apparent by 14 days post-injury when the level of neuronal death following resection was substantially greater than that seen in crush injury. For nerve resection, the peak of neuronal death at 14 days post-resection was followed by a maximal T cell response one week later at 21 days. Differences in the level of neuronal death between the two injuries across the time course tested reflected differences in cumulative neuronal loss at 49 days post-injury. Altogether, these data suggest that the trafficking of T cells to the injured FMN is dependent upon the intensity of peripheral nerve injury and associated neuronal death.

Age and facial nerve axotomy-induced T cell trafficking: Relation to microglial and motor neuron status☆

“…This could account for the elevated levels of perineuronal microglial phagocytic seen between days 14 – 21 post-resection in the 52 week group. It is noteworthy that in both young and aging animals, the present data are consistent with previous studies from our lab and others showing that whether facial motor neurons undergo injury by crush, transaction or resection, the rate of dead motor neurons identified by perineuronal mircroglial phagocytic clusters appear to consistently peak at day 14 post-injury (Moller et al, 1996; Raivich et al, 1998; Ha et al, 2008). …”

“…The fate of neurons, measured by the cumulative motor neuron loss at day 28 was not different between the groups (Figure 3), despite the fact that the kinetics motor neuron death identified by perineuronal microglial phagocytic clusters between 7 and 28 days post-resection differed between the age groups (Figure 1B). Therefore, the higher levels of T cell trafficking into the injured FMN of 52 week mice is not attributable to higher levels of injury-induced neuronal damage in the older mice as we had expected (Ha et al, 2008). Surprisingly, the effects of aging on motor neuron survival following facial nerve axotomy had not been reported in the literature.…”

“…In a series of two studies, Vaughan showed that compared to rats 3 months of age, injured facial motor neurons of 15 month old rats had decreased recovery rates of enzymatic activity for acetylcholinesterase and cytochrome oxidase, as well as smaller increases in nuclear size associated with functional recovery after nerve crush injury (Vaughan, 1990, 1992). Our research indicates the level of T cell trafficking into the axtomized FMN is related to the the severity of neuronal injury (Ha et al, 2008). Together, these data suggest that if facial motor neurons of aging mice are more vulnerable to damage than those of younger mice, then higher levels of T cells trafficking to the FMN of aging mice may be necessary to maintain comparable levels of neuronal survival to younger mice.…”

“…As noted earlier, Vaughan (1990, 1992) found that 15 month old rats had decreased recovery rates of enzymatic activity for acetylcholinesterase and cytochrome oxidase, and smaller increases in nuclear size associated with functional recovery after nerve crush injury than 3 month old rats. Neuronal survival was not assessed in those studies (Vaughan 1990, 1992), most likely because facial nerve crush does not induce notable neuronal loss as is seen following nerve resection (Ha et al, 2008). Tracking the numbers of dead motor neurons by quantifying CD11b + perineuronal microglial phagocytic clusters at days 7, 14, 21 and 28 provides 4 cross-sectional snapshots in time, where each time point represents the rate of neuronal death at that specific time point post-injury.…”

Molecular Inflammatory Mediators in Peripheral Nerve Degeneration and Regeneration

“…Other mediators, such as nitric oxide, as well as inflammatory cells, such as macrophages and T cells, which were not reviewed in this article, also play significant roles [3,[132][133][134] . However, the present review allows us to draw a general framework of the molecular inflammatory regulation of nerve degeneration/regeneration ( fig.…”