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. An appreciation of the role of pro-inflammatory cytokines and inflammation in both acute neuronal insult and chronic neurodegenerative disease has developed in recent years. 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. These cells survey the neural environment and rapidly respond to environmental changes. With changes in neuronal activity, presence of pathogen, or a mechanical/physical injury, microglia respond with dramatic changes in cell morphology and increased expression of macrophage markers. There is heterogeneity of microglia responses and the characterization of functional differences between the various microglia structural phenotypes continues to be a major question in addressing the functional role of these cells in brain injury. In characterizing the impact of neuroinflammation, critical questions regarding the cellular source of pro-inflammatory cytokines and inflammatory factors have been raised. The brain has two indigenous sources of brain macrophages (a general term encompassing all phagocytic cells, including activated microglia resident to the brain and blood-derived monocytes entering the brain upon vascular injury). Once in the brain, the macrophages are morphologically indistinguishable. 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. One structurally distinct difference between the hippocampal regions was the presence of reactive and activated phagocytic microglia in the DG;while, within the CA1 region, the microglia response was characterized morphologically by a ramified process bearing phenotype. The localized amoeboid microglia contact with dentate neurons may serve to present the neuron as a target for additional extraneuronal signals and increase the likelihood of death. While, in the CA1 region, the process bearing microglia are not expressing such signals may instead provide factors serving in a neurotrophic role for the pyramidal neurons. In using this model, we have been able to identify differential roles for pro-inflammatory cytokines in neuronal death or survival. For example, we previously demonstrated a potential threshold effect for tumor necrosis factor alpha produced by microglia in the activation of TNF receptors on neurons determining subsequent signaling for death or survival. The response heterogeneity of resident microglia as identified by immunohistochemical methods suggested a distinction between the production level of TNFalpha by microglia and the expression pattern of TNF receptors on neurons with a sequential internalization of the TNFp75 receptor followed by internalization of the TNFp55 receptor required for neuronal apoptosis in the hippocampus. Thus, TNFR localization can serve as a critical marker for distinguishing the effects of TNF alpha in the brain. This work suggested that efforts to modulate the adverse effects of TNF on the nervous system require targeting of the signaling cascade downstream of receptor activation rather than an inhibition of TNF (1). One possible target identified is FLIP. Using this model, we have also determined that the brain can induce the endogenous production of anti-inflammatory factors for protection including the production of interleukin-1 receptor antagonist to down-regulate the overproduction of interleukin-1 and thus, inhibit receptor activation and cell death. To further examine the impact of resident microglia cells on neuronal death, we have established an in vitro slice model of the striatum to examine the modulatory effects of microglia on neurons expressing the mutant Huntintin gene. Preliminary data suggests that we can identify activation state specific effects of microglia for detrimental or neuroprotective outcomes. Our more recent work with this model has focused on identifying unique factors upregulated by the brain for neuroprotection. In the hippocampus, the CA1 pyramidal neurons are highly vulnerable to ischemic/hypoxic insults. 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. Using both immunohistochemical analysis and mice deficient in insulin like growth factor receptor, we confirmed a role for insulin like growth factor-1 (IGF-1) in CA1 pyramidal neuron survival (3). In addition, we demonstrated activation of Akt in CA1 neurons as a major endogenous mechanism for survival against non-ischemic insults (3). Using this model we have been able to demonstrate neuroprotection of the dentate granule neurons with voluntary exercise and the preliminary data suggests that this is due to an up-regulation of interleukin-6. Each of these studies demonstrate a differential effect of pro-inflammatory cytokine signaling and heterogeneity of microglia leading to neuronal death or neuronal survival. 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. Further work has been conducted in collaborations to continue to identify and understand the role of neuroinflammation and the microglia or astrocyte response in various neuropsychiatric disorders and neurodegenerative diseases (2 ).
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