Program in Cellular and Molecular Medicine, Immune Disease Institute, Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2009 Dec 8;106(49):20960-5. doi: 10.1073/pnas.0911405106. Epub 2009 Nov 20.
During injury to the nervous system, innate immune cells mediate phagocytosis of debris, cytokine production, and axon regeneration. In the neuro-degenerative disease amyotrophic lateral sclerosis (ALS), innate immune cells in the CNS are activated. However, the role of innate immunity in the peripheral nervous system (PNS) has not been well defined. In this study, we characterized robust activation of CD169/CD68/Iba1+ macrophages throughout the PNS in mutant SOD1(G93A) and SOD1(G37R) transgenic mouse models of ALS. Macrophage activation occurred pre-symptomatically, and expanded from focal arrays within nerve bundles to a tissue-wide distribution following symptom onset. We found a striking dichotomy for immune cells within the spinal cord and PNS. Flow cytometry and GFP bone marrow chimeras showed that spinal cord microglia were mainly tissue resident derived, dendritic-like cells, whereas in peripheral nerves, the majority of activated macrophages infiltrated from the circulation. Humoral antibodies and complement localized to PNS tissue in tandem with macrophage recruitment, and deficiency in complement C4 led to decreased macrophage activation. Therefore, cross-talk between nervous and immune systems occurs throughout the PNS during ALS disease progression. These data reveal a progressive innate and humoral immune response in peripheral nerves that is separate and distinct from spinal cord immune activation in ALS transgenic mice.
在神经系统损伤过程中，先天免疫细胞介导碎片吞噬、细胞因子产生和轴突再生。在神经退行性疾病肌萎缩侧索硬化症（ALS）中，中枢神经系统中的先天免疫细胞被激活。然而，先天免疫在周围神经系统（PNS）中的作用尚未得到很好的定义。在这项研究中，我们描述了在 ALS 的突变 SOD1(G93A)和 SOD1(G37R)转基因小鼠模型中，PNS 中 CD169/CD68/Iba1+巨噬细胞的强烈激活。巨噬细胞的激活发生在症状出现之前，并在症状出现后从神经束内的局灶性排列扩展到组织广泛分布。我们发现脊髓和 PNS 中的免疫细胞存在显著的二分法。流式细胞术和 GFP 骨髓嵌合体显示，脊髓小胶质细胞主要是组织驻留衍生的、树突状样细胞，而在外周神经中，大多数激活的巨噬细胞从循环中浸润。体液抗体和补体与巨噬细胞募集并行定位于 PNS 组织，补体 C4 的缺乏导致巨噬细胞激活减少。因此，在 ALS 疾病进展过程中，神经系统和免疫系统之间的相互作用发生在整个 PNS 中。这些数据揭示了 ALS 转基因小鼠中，外周神经中存在进行性先天和体液免疫反应，与脊髓免疫激活分离且不同。
