Immunoregulation of the central response to peripheral nerve injury: motoneuron survival and relevance to ALS

Abstract

Facial nerve axotomy (FNA) in immunodeficient mice causes significantly more facial motoneuron (FMN) loss relative to wild type (WT), indicating that the immune system is neuroprotective. Further studies reveal that both CD4+ T cells and interleukin 10 (IL-10) act centrally to promote neuronal survival after injury. This study first investigated the roles of IL-10 and CD4+ T cells in neuroprotection after axotomy. CD4+ T cell-mediated neuroprotection requires centrally-produced IL-10, but the source of IL-10 is unknown. Using FNA on IL-10 reporter mice, immunohistochemistry was employed to identify the IL-10 source. Unexpectedly, axotomy induced astrocyte production of IL-10. To test if microglia- or astrocyte-specific IL-10 is needed for neuroprotection, cell-specific conditional knockout mice were generated. Neither knockout scenario affected FMN survival after FNA, suggesting that coordinated IL-10 production by both glia contributes to neuroprotection. The effect of immune status on the post-FNA molecular response was studied to characterize CD4+ T cell-mediated neuroprotection. In the recombinase-activating gene2 knockout (RAG-2-/-) mouse model of immunodeficiency, glial microenvironment responses were significantly impaired. Reconstitution with CD4+ T cells restored glial activation to normal levels. Motoneuron regeneration responses remained unaffected by immune status. These findings indicate that CD4+ T cell-mediated neuroprotection after injury occurs indirectly via microenvironment regulation. Immunodysregulation is evident in amyotrophic lateral sclerosis (ALS), and FMN survival after FNA is worse in the mutant superoxide dismutase (mSOD1) mouse model of ALS. Further experiments reveal that mSOD1 CD4+ T cells are neuroprotective in RAG-2-/- mice, whereas mSOD1 whole splenocytes (WS) are not. The third aim examined if the mSOD1 WS environment inhibits mSOD1 CD4+ T cell glial regulation after axotomy. Unexpectedly, both treatments were equally effective in promoting glial activation. Instead, mSOD1 WS treatment induced a motoneuron-specific death mechanism prevalent in ALS. In conclusion, the peripheral immune system regulates the central glial microenvironment utilizing IL-10 to promote neuronal survival after axotomy. Astrocytes, specifically, may be responsible for transducing peripheral immune signals into microenvironment regulation. Additionally, the immune system in ALS may directly participate in disease pathology.