The presence of activated microglia during almost any neurological insult and the reliance on, and possible over-interpretation of, data obtained from in vitro systems has lead to the assumption that activated microglia and associated inflammatory responses are harmful to the brain. Recent work, however, has clearly demonstrated that the cellular activities are, for the most part, beneficial. It is when the strict regulatory control normally imposed on them is altered that these cells may begin to show detrimental effects. One could speculate that such functions could be related to senescence and the inability to perform normal activities or the production of pro-inflammatory cytokines exceeding the down-regulatory capacity of the system with either an acute or chronic induction. Classification as beneficial or detrimental oversimplifies the interactions between diverse cell types of the brain and the signaling cascades they initiate. Various families of cytokines, growth factors, and chemokines influence the apoptotic or survival pathways of neurons and the inflammatory state of the CNS. Understanding signaling pathways activated by such factors continues to increase; however, it is still unclear which specific pathways regulate inflammatory processes in more chronic neurodegeneration and neuroimmunological diseases. What is becoming clear is that there is a complex and dynamic response of the brain to regulate inflammatory processes and maintain a normal homeostatic level. Any role in dysregulation is complex and due to the overlapping, synergizing, and antagonizing effects of various factors. This then requires consideration of the process as a balanced network where subtle modifications can shift the cells toward disparate outcomes, such as death, proliferation, migration, the induction of inflammation, or the inhibition of immune responses.
In addition, it is possible that the resident microglia of the brain parenchyma are more receptive to the regulatory controls of the environment and that, many of the damaging effects observed, stem from infiltrating peripheral macrophages recruited to the site of damage. This may explain the dichotomy of microglial responses observed: the rather diffuse response of process bearing microglia throughout the brain but the more activated morphology seen at focal injury sites. In addition, the possibility exists that activated microglia are not committed to a particular behavioral phenotype but, rather, may be able to vacillate between destructive and supportive phenotypes. In this case, characterizing the temporal pattern of such changes becomes important when interpreting data on the nature of the microglial response and how it might play a role in neurotoxicity or neuroprotection.
A significant amount of our current knowledge on microglia comes from in vitro studies. While such studies can provide information on the cellular mechanisms of a specific response, they do not reflect the heterogeneity of microglia or the complexity of their responses in vivo. Responses observed in vitro will be one-dimensional, given that the cells are deprived of their physiological environment and often stimulated on only a single receptor, such as with LPS. Thus, their use within the context of toxicology may be limited to the ability to determine if the exposure to an environmental agent can directly induce a microglial response. This, however, does not conclude that a similar response will occur in vivo or with environmentally relevant exposures and byproducts. The net outcome of the multiple microglia-derived factors remains un-resolved. The continued in vitro and in vivo work clearly demonstrates that the network of effects and the interactions between the various cell types of the brain, as well as a contribution from non-CNS- resident cells, requires that any evaluation of the process employ multiple endpoints. The final outcome and effect of the process is dependent upon the nature of the insult and the underlying biological state of the organism, including age, genetic background, stress level, disease, drug, and environmental exposure history. The physiological and pathological nature of interactions between the immune and nervous systems is different from the localized response of resident immune cells in the brain (104). Each should be considered individually, as well as, in concert, when evaluating clinical and experimental data with regards to determining the detrimental or beneficial consequence of the response.
The source and history of CNS-resident macrophage populations becomes of importance in determining the impact of exposure-related changes. For example, if the source of amoeboid macrophages is from a blood-borne population, then the systemic effects of exposure to drugs or environmental agents becomes of issue if a challenge or injury occurs that recruits blood-borne cells. Conversely, if the source of macrophages is from a self-renewing or a long-lived source located within the CNS, this then reflects the length of time that the cell has had to adapt to any environmental differences (i.e. matrix components, cellular contact, etc.) or homeostatic signals (i.e. extracellular ligands) from the environment. As has been assumed for development of the nervous system with regards to neurons and neural connections, the developmental ontogeny of microglia and the limited turnover of these cells suggest that development may also reflect a vulnerable period for disruption that may manifest as dysfunction over a long period of time. Additionally, the demonstration of microglia senescence suggests a second vulnerable period occurring in the aged population.
Our understanding of the complexity of the monocyte populations throughout the body, the heterogeneity of microglia cells, the possible contribution of cells recruited from the periphery or those activated within the brain parenchyma, and the multiple factors involved in the regulation of neuroinflammation, sets a daunting task in the design and interpretation of studies evaluating the impact of environmental exposure. While it is tempting to morphologically examine the response of glia or to measure levels of pro-inflammatory cytokines, each in isolation, it is clearly evident from the current state of the field that this will offer little understanding of the system. Within the field of neurotoxicology, there are a few laboratories trying to use an integrated approach to understand how neuroinflammation and alterations in this process may contribute to neurotoxicity. Of interest is the evolving approach of not only determining the impact on degeneration but also on neuronal survival. The research efforts within neurotoxicology cited above represent work conducted with this broader perspective in mind and, as such, offer a framework for future studies.