The Contribution of Microglia to Neurologic Disorders
Monday, June 4, 2007
Presented by the Brain Dysfunction and Neuroimmunology Discussion Group
Organizers: Juan Lafaille, New York University; James Salzer, New York University
Speakers: Monica Carson, University of California, Riverside; Wenbiao Gan, New York University; Bryan Hains, Yale University
The Neuroimmunology Discussion Group focuses on the interface between the immune system and the nervous system both in the brain and in the periphery, in normal and pathological conditions. This highly interdisciplinary group seeks to bring together immunologists and neuroscientists interested in exploring the intersection of these two fields in periodic meetings that will include discussions of basic, clinical, and translational aspects of this emerging field.
Acutely-infiltrating macrophages but not adult CNS-resident microglia are neurotoxic following LPS/IFNg activation in vivo
University of California
Microglial activation coupled with acute peripheral macrophage infiltration is a prominent feature of many CNS insults and chronic neurodegenerative disorders. Due to the absence of cell-type specific histological markers, the differential contributions of resting microglia and infiltrating macrophages toward neurodegeneration have been difficult to identify in vivo. Conversely, in vitro studies have generally relied on microglial cell lines or primary neontal microglia that have differentiated and have been cultured for extended periods of times in the absence of normal CNS cues (neuronal and glial). Using these in vitro model systems, numerous studies have demonstrated that LPS/IFNg-activated microglia are highly toxic to embryonic hippocampal neurons. Conversely, intracerebral injections of LPS/IFNg into the adult murine CNS, lead to a reproducible, robust activation of CNS-resident microglia coupled with a large influx of activated macrophages. This self-resolving inflammatory response causes no detectable neurotoxicity and peaks within 24 hours. We therefore, hypothesized that:
(a) microglial phenotype and function in the healthy adult CNS is determined by their differentiation in the presence of both neuronal and glial cues;
(b) activation of "properly educated" microglia within the context of the normal CNS might not lead to neurotoxicity;
(c) the effector functions of resident microglia and infiltrating macrophages may differ even when isolated from the same inflamed CNS.
To test this three-part hypothesis, we used flow cytometry to isolate and separate activated resident microglia and infiltrating macrophages from the same LPS/IFNg injected brains based on their differential expression of CD45. Isolated cells were co-cultured for two days with 1 or 2 week old embryonic hippocampal neurons. Strikingly, the numbers of viable neurons, the numbers and lengths of dendritic spines nor the number of synapses was altered by the presence of LPS/IFNg-activated adult microglia. By contrast, few neurons survived when co-cultured with CNS-infiltrating macrophages. Unexpectedly, TNFa was strongly induced in the healthy microglia:neuronal co-cultures but not in the neurotoxic macrophage co-cultures. These results indicate that microglia are a tissue macrophage specialized to support neuronal function and that the normal CNS is required to generate their CNS-supportive phenotype.
Coauthors: Tina V. Bilousova, Shweta S. Puntambekar, Janelle Crane, Iryna M. Ethell
Microglial Response in Brain Injury
Wenbiao Gan, PhD
New York University
Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact living mouse cortex. Upon traumatic brain injury, microglial processes rapidly converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. Both in vivo and in vitro experiments indicate that ATP released from astrocytes