Impact of peripheral immune status on central molecular responses to facial nerve axotomy

•Immunodeficient mice have a suppressed glial response after facial nerve axotomy.•Neuroprotective WT CD4+ T cells regulate the glial microenvironment.•Intrinsic motoneuron regeneration response is independent of immune status.•mSOD1 whole splenocytes induce cell death pathways after axotomy.•New ro...

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Published in:	Brain, behavior, and immunity Vol. 68; pp. 98 - 110
Main Authors:	Setter, D.O., Runge, E.M., Schartz, N.D., Kennedy, F.M., Brown, B.L., McMillan, K.P., Miller, W.M., Shah, K.M., Haulcomb, M.M., Sanders, V.M., Jones, K.J.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Inc 01-02-2018
Subjects:	Amyotrophic lateral sclerosis Axotomy Motoneuron Nerve injury T cells Nerve injury Amyotrophic lateral sclerosis Axotomy Motoneuron T cells
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Summary:	•Immunodeficient mice have a suppressed glial response after facial nerve axotomy.•Neuroprotective WT CD4+ T cells regulate the glial microenvironment.•Intrinsic motoneuron regeneration response is independent of immune status.•mSOD1 whole splenocytes induce cell death pathways after axotomy.•New role proposed for the immune system in neurodegenerative diseases. When facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2−/−) mice, there is greater facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2−/− mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2−/− mice with lymphocytes from the mutant superoxide dismutase (mSOD1) mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways. Gene expression profiles of the axotomized facial motor nucleus were assessed from RAG-2−/− mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2−/− + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.
ISSN:	0889-1591 1090-2139
DOI:	10.1016/j.bbi.2017.10.005