Excessive inflammatory response is a deleterious feature of major central nervous system (CNS) pathologies, most notably, stroke, spinal cord/brain injury and chronic neurodegenerative conditions, such as multiple sclerosis, Alzheimer’s and Parkinson’s diseases. CNS inflammation is mediated by innate immune cells, i.e., resident glial cells and infiltrating leukocytes. Upon activation these cells generate reactive oxygen species (ROS), cytokines, enzymes and other inflammatory agents that exert a vast array of adverse effects on CNS tissue. Therefore, the understanding of mechanisms that control neuroinflammation is critical for the development of rational and efficient therapeutic strategies to combat CNS pathologies.
Because neuroinflammation may greatly exacerbate tissue damage, the modulation of neuroinflammation is of considerable interest for devising new strategies for clinical intervention. Glial cells, i.e, microglia and astrocytes, are the primary innate immune cells of the CNS, and together with infiltrating leukocytes are responsible for the instigation of neuroinflammation. In particular, astrocytes are the most abundant glial cells that constitute approximately half of CNS cells, and are structurally and functionally coupled to all major cellular elements including neurons, the myelin-oligodendrocyte unit and the vascular compartment. Consequently, inflammatory reactions elicited in astrocytes have profound effects on CNS parenchyma. Like in other innate immune cells, inflammatory reactions in astrocytes are primarily mediated by a family of structurally related transmembrane pattern recognition receptors, Toll-like receptors (TLRs). These receptors recognize a variety of exogenous and endogenous ligands, and trigger signaling programs that culminate in the generation of inflammatory mediators. My research centers on the mechanisms that control the activity of TLR3 and TLR4 in astrocytes. TLR3 ligands include double stranded RNA (dsRNA) structures of viral and/or mammalian origin, whereas TLR4 ligands include bacterial lipopolysaccharide (LPS), and several molecules released from damaged tissues. Consequently, these receptors are likely to play a major role in a wide spectrum of neuropathologies. We have recently shown that the exposure of cultured astrocytes to dsRNA or LPS results in a robust but transient upregulation of proinflammatory cytokine gene expression. Moreover, the cells become refractory to subsequent stimulation indicating the existence of negative feedback mechanisms that control the receptor signaling. We are currently seeking to decipher these feedback mechanisms. Understanding these mechanisms has immense therapeutic potential to control neuroinflammation through targeted manipulation of TLR signaling pathways.
Lab Personnel & Collaborators
Laboratory of Molecular Neuropathology
Tel: (304) 293-6621
Michal Kraszpulski, Ph.D., Research Instructor
Alicja Krasowska, M.Sc., Lecturer
Saritha Krishna, Grad Student
Isaac James, Undergrad Student
Laszkiewicz I, Mouzannar R, Wiggins RC, Konat GW (1999) Delayed oligodendrocyte degeneration induced by brief exposure to hydrogen peroxide. J Neurosci Res 55:303-310.
Mouzannar R, Miric SJ, Wiggins RC, Konat GW (2001) Hydrogen peroxide induces rapid digestion of oligodendrocyte chromatin into high molecular weight fragments. Neurochem Int 38:9-15.
Konat GW, Mouzannar R, Bai H (2001) Higher order chromatin degradation in glial cells: The role of calcium. Neurochem Int 39:179-186.
LoPresti P, Konat GW (2001) Hydrogen peroxide induces transient dephosphorylation of tau protein in oligodendrocytes. Neurosci Lett 311:142-144.
Konat GW (2002) Higher order chromatin degradation: Implications for neurodegeneration. Neurochem Res 27:1439-1443.
Bai H, Konat GW (2003) Hydrogen peroxide mediates higher order chromatin digestion. Neurochem Int 42:123-129.
Konat GW (2003) H2O2-induced higher order chromatin degradation: A novel mechanism of oxidative genotoxicity. J Biosci 28:57-60.
Konat GW, Krasowska A (2004) Hypochlorous acid activates signaling pathways and induces gliotic response in astrocytes. J Neurochem 90:CP1-02.
Krasowska A, Konat GW (2004) Vulnerability of brain tissue to inflammatory oxidant, hypochlorous acid. Brain Res 997:176-184.
Konat GW, Krasowska A (2004) Double stranded RNA suppresses myelin gene expression in vitro. J Neurochem 90:BP9-08.
Banaszewska M, Konat GW (2006) Nucleotides induce higher order chromatin degradation. Mol Cell Biochem 282:39-43.
Konat GW, Kielian T, Marriott I (2006) The role of Toll-like receptors in CNS response to microbial challenge. J Neurochem 99:1-12.
Krasowska A, Banaszewska M, Kraszpulski M, Konat GW (2006) Kinetics of inflammatory response induced by ligation of TLR3 and TLR4 in astrocytes. J Neurosci Res (Epub).
Konat GW, Banaszewska M, Krasowska A (2006) Negative feedback regulation of TLR signaling in astrocytes. J Neurochem PMS05-15