Neuroimmunotoxicology: autoimmunity, inflammation, age, environmental agents

炎症是机体对感染、损伤和创伤的正常反应。在这个框架中，炎症可以被视为一系列复杂的局部免疫反应，用于应对对细胞微环境的威胁。这些反应的启动是为了中和入侵的病原体，修复受损的组织，并促进伤口愈合以恢复组织的动态平衡。神经炎性反应在帕金森氏病、阿尔茨海默病和亨廷顿病等各种神经退行性疾病以及包括创伤和中风在内的脑损伤中都有重要的作用。然而，识别和描述神经保护和损伤方面的反应仍然是一个主要的幻觉问题。虽然神经炎症一直被认为是继发性损伤的媒介，但局部免疫反应对创伤组织也有有益的影响。 小胶质细胞是大脑中常驻的单核巨噬细胞，在健康的中枢神经系统中具有高度的异质性。它们只占大脑细胞总数的10%；然而，它们有多种形态和潜在的功能特征，这取决于它们所处的环境。不同的小胶质细胞结构表型之间的功能差异的表征仍然是解决这些细胞的功能作用的主要问题。一个限制是缺乏一个好的模型系统，在这个系统中，脑巨噬细胞的反应仅限于驻留的小胶质细胞，而不涉及渗透的巨噬细胞。这也限制了对脑巨噬细胞反应在神经退行性疾病中的作用的理解，以及开发成功的治疗方法。我们已经在小鼠中建立了这样的模型，利用已知的神经毒剂有机金属三甲基锡(TMT)，在没有血脑屏障改变和血媒细胞渗透的情况下，创建损伤的局部部位。利用这个模型，我们能够研究小胶质细胞在齿状颗粒神经元细胞死亡和清除中的作用，以及它们在促进对缺血敏感的海马锥体神经元存活方面的作用。在我们的TMT损伤模型中，这些细胞是幸免的，这一事实使我们能够检查这些神经元中发生的潜在关键事件，以促进生存。对这些因素的识别将有助于将这些事件转化为中风等缺血条件下的治疗干预。损伤或损伤的来源之间的区别变得重要，因为CA1神经元参与了阿尔茨海默氏病的病理过程，而在没有缺血的情况下，CA1神经元参与了小鼠的后遗症模型。因此，了解CA1神经元在受损环境中存活的内源性机制可以导致治疗干预策略，将细胞损失降至最低。 使用切片培养模型，我们研究了小胶质细胞在突变型Huntingtin基因表达相关的神经细胞死亡中的作用。在这个模型中，我们证明了小胶质细胞的早期神经保护作用，以及小胶质细胞在清除受损神经突起中的作用。 正常大脑黑质内小胶质细胞数量的增加导致了一种推测，认为帕金森氏病与慢性神经炎和多巴胺神经元丢失有关。这群神经元对环境中的杀虫剂暴露也很敏感。由于缺乏相关的动物模型，对慢性神经炎的影响的了解一直受到限制。为了解决这个问题，我们利用HIV转基因大鼠来检查不同脑区炎症状态的变化，并将其与小胶质细胞的形态表型和任何神经元死亡的证据相关联。

Inflammation is a normal response of the organism to infection, injury, and trauma. In this framework, inflammation can be viewed as a complicated series of local immune responses that serve to deal with a threat to the cellular microenvironment. Such reactions are initiated to neutralize invading pathogens, repair injured tissues, and promote wound healing to restore tissue homeostasis. A Significant contributions from neuroinflammatory responses have been implied in various neurodegenerative diseases such as Parkinsons Disease, Alzheimers Disease, and Huntington Disease, as well as brain injury including trauma and stroke. However, identifying and characterizing the neuroprotective versus the injurious aspects of the response still remains a major illusive question. While neuroinflammation has been considered a mediator of secondary damage, the local immune response also has beneficial effects on the traumatized tissue. Microglia serve as the resident mononuclear phagocytes of the brain and are highly heterogeneous within the healthy CNS. They comprise only 10% of the total cell population of the brain; yet, they have multiple morphological and potential functional profiles depending on their environment. Characterization of functional differences between the various microglia structural phenotypes continues to be a major question in addressing the functional role of these cells. One limitation has been with the lack of a good model system where the brain macrophage response is limited to resident microglia and does not involve infiltrating macrophages. This has also served as a limitation in both understanding the role of a brain macrophage response in neurodegenerative disease and developing successful therapeutic approaches. We have established such a model in the mouse by utilizing a known neurotoxicant, the organometal, trimethyltin (TMT), to create focal sites of injury in the absence of an altered blood brain barrier and infiltration of blood borne cells. Using this model we are able to examine the role of microglia in the cell death and clearance of dentate granule neurons as well as their role in promoting survival of hippocampal pyramidal neurons susceptible to ischemia. The fact that these cells are spared in our TMT model of injury allows us to examine potential critical events occurring in these neurons to promote survival. The identification of such factors would then be beneficial in translating these events to a therapeutic intervention under ischemic conditions such as stroke. A distinction between the source of the insult or injury becomes important in that CA1 neurons are involved in the pathology of Alzheimers disease and in a mouse model of tauopathy in the absence of ischemia. Thus, understanding the endogenous mechanisms utilized by CA1 neurons to survive within an injured environment can lead to therapeutic intervention strategies to minimize cell loss. Using a slice culture model, we have examined the contribution of microglia to the neuronal cell death associated with expression of the mutant Huntingtin gene. In this model we have demonstrated an early neuroprotective effect of microglia and a role for microglia in the clearance of damaged neurites. The elevated number of microglia within the substantia nigra in the normal brain has lead to a speculation associating chronic neuroinflammation and loss of dopamine neurons in Parkinson's Disease. This population of neurons is also sensitive to environmental pesticide exposure. Understanding the impact of chronic neuroinflammation has been limited by the lack of a relevant animal model. To address this question, we utilized the HIV transgenic rat to examine changes in the inflammatory status of distinct brain regions and to correlate this with the morphological phenotype of microglia and any evidence of neuronal death (1).