Page - (000007) - in Advances in Neuroimmunology

vii Preface to “Advances in Neuroimmunology” It is now widely accepted that an innate immune system exists within the brain and plays an important role in both physiological and pathological processes [1,2]. This neuroimmune system is comprised of brain cells that produce and secrete chemicals that are historically considered signaling factors of the peripheral immune system, such as cytokines and chemokines. Cells of the brain, primarily glia cells (e.g., astrocytes and microglia) but also neurons under some conditions, produce a large number of immune factors. In addition, endothelial cells of the brain and peripheral immune cells that enter the brain can contribute to the immune environment of the brain [3]. In general, pathological conditions are associated with elevated levels of neuroimmune factors in the brain, whereas low levels of neuroimmune factors are found in the normal brain. For example, elevated levels of neuroimmune factors in the brain have been reported for a number of conditions including brain injury, infection, neurodegenerative and psychiatric disorders, and drug abuse [4–6]. Considerable effort has been devoted to identifying the neuroimmune factors that play a role in these conditions, but much work is yet to be done, especially with respect to the biological actions of individual neuroimmune factors and their role in specific brain disorders. Neuroimmune factors, like their counterpart in the periphery, produce their biological actions through interactions with cognate membrane receptor systems that translate the chemical signal through the intervention of intracellular signaling pathways. These signaling systems are complex and many have yet to be fully elucidated. Of importance is that during pathological conditions, typically multiple signaling factors are simultaneously present in the cellular environment and may activate different signaling pathways on the same cell. These intracellular pathways may interact, a complexity that is a challenge to an understanding of mechanisms responsible for the biological actions associated with a particular brain condition and the development of specific therapeutic strategies. In this Special issue, recent advances in an understanding of the neuroimmune system of the brain and the actions of neuroimmune factors are presented for ten areas under study; most areas are associated with pathological conditions. Together these studies are illustrative of the breadth and status of the field, the experimental approaches being employed, and areas for future research. The review by Gruol [7], summarizes studies on the effects of three neuroimmune factors, the proinflammatory cytokine IL-6, the chemokine CCL2, and the chemokine CXCL10, on an essential aspect of brain function, synaptic transmission. The goal of these studies is to understand the actions of specific neuroimmune factors on this process. The majority of the studies discussed employ transgenic mice that express elevated levels of a neuroimmune factor (IL-6, CCL2 or CXCL10) in the brain through increased expression by astrocytes. Transgenic mice that express elevated levels of IL-6 in the brain through increased astrocyte expression are also used in studies reported in the original article by Erta et al [8]. Transgenic mice null for astrocyte IL-6 expression are also used. The goal of these studies is to identify the role of astrocyte production of IL-6 in the symptomatology of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis in humans. The review by Mukandala et al [9] summarizes studies that investigate the role of neuroimmune factors in acute and chronic hypoxia, and the consequences of neuroinflammation induced by hypoxia on hippocampal synaptic function. Hypoxia and neuroinflammation are two conditions that play a central role in ischemia. Complex signaling pathways involving the proinflammatory cytokine TNF- alpha and other factors are described along with their proposed roles in hypoxia and altered synaptic function associated with hypoxia. Mori et al. [10] review the current state of knowledge on the expression and actions of two cytokines, IL-13 and IL-4, in the brain. Production of these cytokines by neurons and glia of the brain has been reported, but information is still limited. Both IL-13 and IL-4 can signal through a receptor complex comprised of IL-13 and IL-4 receptor subunits, although IL-4 also interacts with a separate IL-4 receptor. Evidence of a role for one of both of these cytokines in hypoxia, EAE and Parkinson’s disease is presented, along with evidence for modulatory actions on dopaminergic neurons.