Immunodeficiency impairs re-injury induced reversal of neuronal atrophy: Relation to T cell subsets and microglia

Abstract

Following facial nerve resection in the mouse, a substantial number of neurons reside in an atrophied state (characterized by cell shrinkage and decreased ability to uptake Nissl stain), which can be reversed by re-injury. The mechanisms mediating the reversal of neuronal atrophy remain unclear. Although T cells have been shown to prevent neuronal loss following peripheral nerve injury, it was unknown whether T cells play a role in mediating the reversal of axotomy-induced neuronal atrophy. Thus, we used a facial nerve re-injury model to test the hypothesis that the reversal of neuronal atrophy would be impaired in recombinase activating gene-2 knockout (RAG-2 KO) mice, which lack functional T and B cells. Measures of neuronal survival were compared in the injured facial motor nucleus (FMN) of RAG-2 KO and wild-type (WT) mice that received a resection of the right facial nerve followed by re-injury of the same nerve 10 weeks later ("chronic resection + re-injury") or a resection of the right facial nerve followed by sham re-injury of the same nerve 10 weeks later ("chronic resection + sham"). We recently demonstrated that prior exposure to neuronal injury elicited a marked increase in T cell trafficking indicative of a T cell memory response when the contralateral FMN was injured later in adulthood. We examined if such a T cell memory response would also occur in the current re-injury model. RAG-2 KO mice showed no reversal of neuronal atrophy whereas WT mice showed a robust response. The reversal of atrophy in WT mice was not accompanied by a T cell memory response. Although the number of CD4 + and CD8 + T cells in the injured FMN did not differ from each other, double-negative T cells appear to be recruited in response to neuronal injury. Re-injury did not result in increased expression of MHC2 by microglia. Our findings suggest that T cells may be involved in reversing the axotomy-induced atrophy of injured neurons.

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

“…As statistical analysis revealed that the distribution of the data was not normal, Spearman's rank correlation analysis was used to determine the relationship between T cells and neuronal death (as measured by the number of microglial phagocytic clusters). For neuronal cell counts, facial motor neurons were quantified in 8 representative sections of the FMN, as described previously (Deboy et al, 2006;Ha et al, 2007a). The medial nucleus, which receives innervation from the auricular branch of the facial nerve, remained uninjured and thus was excluded from the analysis.…”

Effects of facial nerve axotomy on Th2- and Th1-associated chemokine expression in the facial motor nucleus of wild-type and presymptomatic mSOD1 mice

“…Furthermore, PACAP mRNA is expressed by injured mouse FMN after facial nerve axotomy (Armstrong et al ., 2003) and PACAP increases Th2-associated chemokine expression in cultured murine microglia (Wainwright et al ., 2008). Since CD4 + T cells are present in the facial motor nucleus after injury (Ha et al ., 2007) and the Th2, but not the Th1, effector subset mediates FMN survival (Deboy et al ., 2006), we hypothesized that Th2-associated chemokines would be expressed in the facial motor nucleus after facial nerve axotomy. To delineate this mechanism, we studied the expression of Th2-associated chemokine, CCL11, and Th1-associated chemokine, CXCL11, in the facial motor nucleus after facial nerve axotomy.…”

“…After facial nerve axotomy, the number of astrocytes in the facial motor nucleus that were immunoreactive for CCL11 increased significantly at time points consistent with significant T cell infiltration (Raivich et al ., 1998; Ha et al ., 2007). There is a growing literature demonstrating chemokine expression by astrocytes as a result of neuronal injury (Katayama et al ., 2009; Khorooshi et al ., 2008; Babcock et al ., 2003).…”

“…Additionally, previous studies found a maximum increase in T cell infiltration of the axotomized mouse facial motor nucleus between 7–21 days after injury (Raivich et al ., 1998). Furthermore, it has been demonstrated that CD4 + T cells infiltrate the facial motor nucleus after facial nerve injury (Ha et al ., 2007). In support of these findings, our laboratory has shown that CNS resident microglia are necessary to reactivate CD4 + T cells centrally (Byram et al ., 2004), suggesting that a mechanism must exist for peripheral CD4 + T cell recruitment to the injured facial motor nucleus from the draining cervical lymph nodes.…”

Reversal of Neuronal Atrophy: Role of Cellular Immunity in Neuroplasticity and Aging

“…Reinjuring the facial nerve stimulates a reversal in the atrophic status of the injured neurons, causing an increase in both their size and number [7]. As described below, data from our research suggests that under normal physiological conditions, the reversal of atrophy and the ability of reinjured facial motor neurons to regain their normal phenotype is dependent on a normal functioning cellular immune system [8,9]. To our knowledge, this is the only model of neuronal atrophy reversal that has been studied in the context of immunity or linked to immune function.…”