Professor, Department of Pathology
Microglia are resident brain macrophages and are the prime instigators of several CNS disorders. My laboratory studies the role of microglia in the nervous system inflammation and neurodegeneration using a model of primary human brain cell cultures and several in vivo mouse models3. Pathogenesis-oriented studies and search for potential therapeutic modalities are often the goal. We define the involvement of inflammatory mediators in degenerative human brain diseases including neuroAIDS, multiple sclerosis and Alzheimer’s disease. The disease that we currently focus on is HIV-associated neurocognitive disorder, a nervous system dysfunction directly and indirectly caused by HIV infection and inflammatory activation of microglia and macrophages. We study the involvement of cytokines and chemokines in modulating HIV infection, as well as signal transduction pathways that are activated by HIV in these cells. For example, we have recently identified CD45 tyrosine phosphatase as a constitutive protein expressed in microglial cells that can be targeted by an agonist antibody resulting in suppression of HIV replication and microglial activation1,2. Another area of long interest is a mechanism of human microglial and astrocyte activation by interleukin-1 and the toll-like receptor (TLR) ligands4,5. IL-1 is produced by microglia in response to a variety of different insults and is indispensable for nitric oxide and TNFa production from human astrocytes. IL-1 is responsible for neuronal death during inflammatory degeneration of the human CNS. In contrast, the TLR3 and TLR4 ligands activate a strong anti-viral program, while triggering IL-1 generation. Therefore, we believe that the key to neuroprotection is programming microglia to suppress the production of harmful cytokines while promoting the production of neurotrophic and immunoregulatory mediators. Towards this goal, we have identified a protein factor that enhances the neuroprotective phenotype of microglia by suppressing NF-κB-dependent gene expression while promoting interferon-mediated antiviral pathways. Our long term goal is to understand the mechanism of human glial and neuronal interactions during CNS diseases at the cellular and molecular level, in order to develop molecular therapeutics to promote neuroregeneration.
1: Suh, H. S., Brosnan, C. F., and Lee, S. C. 2009 Chapter 4: TLRs in CNS viral infections. Toll-like Receptors: Roles in Infection and Neuropathology. Kielian, T. ed. in Current Topics in Microbiology and Immunology (In press)
2: Suh, H. S., M. L. Zhao, M. Rivieccio, S. Choi, E. Connolly, Y. Zhao, O. Takikawa, C. F. Brosnan, and S. C. Lee. 2007. Astrocyte indoleamine 2, 3 dioxygenase (IDO) is induced by the TLR3 ligand poly IC: mechanism of induction and role in anti-viral response. J. Virol. 81:9838-9850.
3: Cosenza-Nashat, M. A., M. O. Kim, M. L. Zhao, H. S. Suh, and S. C. Lee. 2006. CD45 isoform expression in microglia and inflammatory cells in HIV-1 encephalitis. Brain Pathol. 16:256-265.
4: Kim, M. O., H. S. Suh, Q. Si, B. I. Terman, and S. C. Lee. 2006. Anti-CD45RO suppresses HIV-1 replication in microglia: role of Hck tyrosine kinase and implications for AIDS dementia. J. Virol. 80:62-72.
5: Lee, S. C., M. A. Cosenza, Q. Si, M. Rivieccio, and C. F. Brosnan. 2005. The CNS: CELLS, TISSUES AND REACTIONS TO INSULT In R. M. Ransohoff and E. N. Benveniste (eds.), CYTOKINES AND THE CNS. CRC Press, Boca Raton, FL.
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Albert Einstein College of Medicine
Jack and Pearl Resnick Campus
1300 Morris Park Avenue
Forchheimer Building, Room 717N
Bronx, NY 10461