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。在各种神经退行性疾病中，如帕金森氏病、阿尔茨海默病、亨廷顿病、艾滋病毒以及包括创伤和中风在内的脑损伤，神经炎性反应都有重要的作用。最近的证据表明，由于重金属和杀虫剂等环境化学物质暴露而造成的脑损伤表明存在炎症成分(Kraft和Harry，2011)。对于这些情况中的每一种，识别和表征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，以及它们在促进海马锥体神经元存活中的作用。小胶质细胞和神经元反应的异质性使我们能够表征导致神经元死亡和神经元存活的神经炎症的独特性质。为了进行比较，我们检查了轻度脑缺血和HIV(2，3)模型中小胶质细胞和炎症反应的不同特性。确定这些因素将有助于将这些事件转化为对缺血/中风或创伤性脑损伤的治疗干预，以将神经元损失降至最低(2，3，5)。 进一步的工作表明，环境因子可以直接诱导小胶质细胞的反应，我们有兴趣确定这些细胞是否代表环境暴露的一般靶细胞(1，4)。如果化学物质暴露起到异常激活小胶质细胞的作用，或者改变了它们对大脑中发生的事件做出适当反应的能力，这可能会对中枢神经系统的功能产生重大影响。因此，我们正在开发模型，使我们能够在对环境制剂的暴露做出反应的框架内检查这些细胞。

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, HIV, as well as brain injury including trauma and stroke. More recent evidence suggests that brain injury as a result of environmental chemical exposure such as heavy metals and pesticides indicates an inflammatory component (Kraft and Harry, 2011). For each of these conditions, 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. The heterogeneity of microglia and neuronal responses allows us to characterize the unique properties of neuroinflammation that contribute to neuronal death and neuronal survival. For comparison, we have examined distinct properties of microglia and inflammatory responses in the brain in models of mild ischemia and HIV (2,3). The identification of such factors would then be beneficial in translating these events to a therapeutic intervention for ischemia/stroke or traumatic brain injury to minimize neuronal loss (2,3,5). Further work demonstrates that environmental agents can induce a response of microglia cells directly, we are interested in determining if these cells represent a general target cell for environmental exposures (1,4). If chemical exposure either serves to aberrantly activate microglia or to change their ability to respond appropriately to events occurring in the brain, this can have a significant effect upon central nervous system functioning. Thus, we are developing models that will allow us to examine these cells within a framework of responding to exposure to environmental agents.