Neuroimmunology Discussion Group
Monday, February 5, 2007
The Chemokine Hypothesis of Interneuronal Communication in the Brain
Martin W. Adler, PhD
Center for Substance Abuse Research, Temple University School of Medicine
Chemokines are a family of small (8-12 kDa) proteins involved in cellular migration and intercellular communication. In addition to being found throughout the immune system, they are now known to exist in the brain. Their presence in glia is well recognized, but their presence in neurons is based on more recent evidence. Although the chemokines and their G protein-coupled receptors are located in both glia and neurons throughout the brain, they are not distributed uniformly. Among the chemokines and their receptors that are arrayed disproportionately in both glia and neurons are CCL2/MCP-1, CXCL12/SDF-1α, CX3CL1/fractalkine, CXCL10/ IP 10, CCL3/MIP-1&apha;, and CCL5/RANTES. They are found in such diverse areas of the brain as the hypothalamus, nucleus accumbens, limbic system, hippocampus, thalamus, cortex, and cerebellum. As with neuropeptides and the classical neurotransmitters, their uneven distribution suggests that there may be functional roles for the "chemokine system," comprised of chemokine ligands and their receptors, in neurotransmission. Our data indicate that the chemokine system can alter the activity of neuronally active pharmacological agents including opioids, cannabinoids, and cocaine. In addition, there is co-localization of some chemokines (e.g., SDF-1α) and neurotransmitters such as dopamine and serotonin, and stimulation of GABAergic synaptic activity in certain neurons. The evidence from our laboratories, when combined with that from others, leads us to propose the following hypothesis: The endogenous chemokine system in the brain acts in concert with neurotransmitter and neuropeptide systems to govern brain function. The chemokine system can thus be thought of as a third major communication system in the brain.
Steroid Hormones, Aging and Microglia: A Functional Analysis Based on Flow Cytometry
Amanda Sierra, PhD
Rockefeller University, Stony Brook University
Microglia are the conductors of the brain innate immune responses, initiating and coordinating the inflammatory response after neuronal degeneration or pathogenic challenge. However, the particular roles of these elusive cells in different disease conditions are poorly understood, mainly because of the lack of appropriate techniques. We have developed a new ex vivo approach that relies on flow cytometry to purify viable microglia from the brain of adult fms-EGFP mice (in which microglia express EGFP), combined with real time RT-PCR and Western blot to accurately quantify microglial responses. Using this ex vivo system, we have shown that adult microglia are a direct target of steroid hormones and that glucocorticoids, through the predominantly- expressed glucocorticoid receptor GR, are the main steroid hormone regulators of microglial activity. Furthermore, steroid hormone receptors are down-regulated after inflammatory challenge, suggesting a prerequisite to suppress the anti-inflammatory actions of endogenous steroid hormones on the immune system, thus contributing to a sustained activation. Our ex vivo system also helped to understand microglial dynamics during the aging process. Aging microglia were characterized by the presence of lipofuscin granules, decreased processes complexity, altered granularity, and increased mRNA expression of both pro-inflammatory and anti-inflammatory cytokines. Following inflammatory challenge, aging microglia exhibited increased expression of cytokines, yet the fold-over-basal response remained constant across age, implying that the inflammatory machinery in aging microglia is functional and adjusted to the basal state. Thus, the low but sustained production of pro-inflammatory cytokines by aging microglia may have a commensura