Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States; Research and Development Service, Richard L. Roudebush VAMC, Indianapolis, IN, United States.
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States; Research and Development Service, Richard L. Roudebush VAMC, Indianapolis, IN, United States.
Brain Behav Immun. 2018 Feb;68:98-110. doi: 10.1016/j.bbi.2017.10.005. Epub 2017 Oct 10.
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.
当在免疫缺陷型重组激活基因-2 敲除（RAG-2）小鼠中进行面神经轴突切断（FNA）时，相对于野生型（WT）小鼠，面神经运动神经元（FMN）的死亡更多。用整个脾细胞重建 RAG-2 小鼠可挽救 FNA 后的 FMN 存活，而 CD4+T 细胞特异性驱动免疫介导的神经保护。有证据表明，免疫失调可能导致肌萎缩侧索硬化症（ALS）中的运动神经元死亡。用 ALS 突变型超氧化物歧化酶（mSOD1）小鼠模型的淋巴细胞重建 RAG-2 小鼠，发现 mSOD1 整个脾细胞环境抑制 FNA 后 mSOD1 CD4+T 细胞介导的神经保护。本研究的目的是描述 CD4+T 细胞对 FNA 后中枢分子反应的影响，然后确定 mSOD1 整个脾细胞是否阻断这些调节途径。从用 WT 或 mSOD1 供体的 CD4+T 细胞或整个脾细胞重建的 RAG-2 小鼠的轴突切断面神经运动核中评估基因表达谱。研究结果表明，免疫缺陷型小鼠在轴突切断后抑制神经胶质细胞激活，而 WT CD4+T 细胞的细胞转移可挽救微环境反应。此外，mSOD1 整个脾细胞受体会观察到对 FNA 的星形胶质细胞激活反应增加。在 RAG-2+ mSOD1 整个脾细胞小鼠中，还观察到运动神经元特异性 Fas 细胞死亡途径的升高。总之，这些发现表明，mSOD1 整个脾细胞不会抑制 mSOD1 CD4+T 细胞对微环境的调节，相反，mSOD1 整个脾细胞可能通过促进神经毒性星形胶质细胞表型或诱导 Fas 介导的细胞死亡途径来促进运动神经元死亡。本研究表明，外周免疫状态显著影响神经损伤后的中枢反应。未来的研究将阐明 mSOD1 整个脾细胞促进细胞死亡的机制，以及抑制这种机制是否可以在损伤和疾病中保留运动神经元的存活。
