Impact of peripheral immune status on central molecular responses to facial nerve axotomy
| Autor: | Karthryn J. Jones, Nicole D. Schartz, Virginia M. Sanders, Whitney M. Miller, Kathryn P. McMillan, Melissa M. Haulcomb, Kishan M. Shah, Elizabeth M. Runge, Deborah O. Setter, Brandon L. Brown, Felicia M. Kennedy |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Programmed cell death Facial motor nucleus Cell Survival T cell medicine.medical_treatment Immunology Biology Neuroprotection Article 03 medical and health sciences Behavioral Neuroscience Mice 0302 clinical medicine medicine Splenocyte Animals Facial Nerve Injuries Facial Nucleus Motor Neurons Cell Death Endocrine and Autonomic Systems Superoxide Dismutase Amyotrophic Lateral Sclerosis Axotomy Nerve injury DNA-Binding Proteins Mice Inbred C57BL Disease Models Animal Facial Nerve 030104 developmental biology medicine.anatomical_structure Cancer research Female medicine.symptom 030217 neurology & neurosurgery Spleen Astrocyte |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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