Faculty / Research
Styliani-Anna E. Tsirka, PhDProfessor
PhD, Biochemistry, Aristotle University of Thesssaloniki, Greece
B.S., Chemistry, Aristotle University of Thesssaloniki, Greece
Neuro-immune interactions: Cross-talk between the nervous and immune systems in health and disease
Traditionally the central nervous system (CNS) has been thought to be ‘immune privileged’ and not interact with the immune system. Increasing evidence however suggests that many neurodegenerative diseases, as well as many acute injuries in the CNS, are characterized by the presence of inflammatory cells in the CNS. An initial response to neuronal injury is evidenced by the activation of CNS microglia. Microglia are antigen-presenting, immune-competent, macrophage-like cells that reside in the CNS and are able to modulate neuronal survival, or are hypothesized to affect neuronal structural changes occurring in response to neuronal activity. Our research interests concern the communication, signaling events and cell-cell interactions between neurons and microglia subsequent to normal or exaggerated stimulation of the CNS that lead to reorganization of neuronal connections in the brain or neuronal cell death.
Stella Tsirka was born and raised in Greece. She received her BS and PhD degrees from the University of Thessaloniki. She then pursued postdoctoral studies at Univ California San Francisco and SUNY Stony Brook, under the mentoring of Drs Phil Coffino and Sid Strickland, respectively. She was appointed Research Assistant Professor in the Department of Psychiatry at SBU in 1998, and joined the Pharmacology faculty in 2000.
Selected peer-reviewed publications or manuscripts in press.
1. S.E. Tsirka, A. Gualandris, D.G. Amaral, S. Strickland (1995) Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue-type plasminogen activator. Nature 377:340-344.
2. S.E. Tsirka, A.D. Rogove, S. Strickland (1996) Tissue plasminogen activator and neuronal cell death. Nature 384:123-124.
3. S.E. Tsirka, T.H. Bugge, J.L. Degen, S. Strickland. Neuronal death in the CNS demonstrates a non-fibrin substrate for plasmin. (1997) Proc.Natl.Acad.Sci.USA 94: 9779-9781.
4. A.D. Rogove, S.E. Tsirka. (1998) Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Curr.Biol.8: 19-25.
5. Y.F. Wang, S.E. Tsirka, S. Strickland, P.E. Stieg, S.G. Soriano, S.A. Lipton. (1998) Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nature Med 4: 228-232.
6. Y.-P. Wu, C.-J. Siao, W. Lu, T.-C. Sung, M.A. Frohman, P. Milev, T.H. Bugge, J.L. Degen, J.M. Levine, R.U. Margolis, S.E. Tsirka. (2000) The tPA/plasmin extracellular proteolytic system regulates hippocampal mossy fiber reorganization through a novel proteoglycan substrate. J. Cell Biol. 148:1295-1304
7. W. Lu, M. Bhasin and S. E. Tsirka. (2002) Involvement of tissue plasminogen activator in both onset and effector phases of experimental allergic encephalomyelitis, J Neurosci: 22: 10781-10789.
8. M Bhasin, M Wu, SE Tsirka. (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis, BMC Immunology, 8 (1): 10 [Epub ahead of print]
9. W.B. Nolin, J. Emmetsberger, N. Bukhari, Y. Zhang, J.M. Levine, and S.E.Tsirka. (2008) tPA-Mediated Generation of Plasmin is Catalyzed by the Proteoglycan NG2, Glia, 56:177-189.
10. Wu, M and SE Tsirka. (2009) Endothelial NOS-deficient Mice reveal dual roles for nitric oxide during Experimental Autoimmune Encephalomyelitis, Glia. 57(11):1204-15 PMCID: PMC2706940
11. Pothakos, K, Robinson, JK, Marsteller, D., Gravanis, I, Dewey, SL., Tsirka SE. (2009) Decreased serotonin levels associated with behavioral disinhibition in tissue plasminogen activator deficient (tPA−/−) mice, Brain Research, 1326:135-42 PMCID: PMC2853966
12. Mirrione MM, Konomos DK, Gravanis, I, Dewey, SL, Aguzzi, A, Heppner, FL, and SE Tsirka. (2010) Microglial ablation and lipopolysaccharide preconditioning affects pilocarpine-induced seizures in mice, Neurobiol Dis. 39(1):85-97 PMCID: PMC2875881
13. Emmetsberger J, Mirrione MM, Zhou C, Siddiq M, Fernandez-Monreal M, Ji K, SE Tsirka (2010) Tissue Plasminogen Activator alters intracellular sequestration of zinc through interaction with the transporter ZIP4, J. Neurosci. 30(19):6538-47 PMCID: PMC2872103
14. Yao Y, Tsirka SE. (2010) The C-terminus of mouse monocyte chemoattractant protein 1 (MCP1) mediates MCP1 dimerization while blocking its chemotactic potency. J Biol Chem. 285:31509-16. PMCID: PMC2951225
15. Sierra A, Encinas JM, Deudero JJP, Chancey JH, Enikolopov G, Overstreet-Wadiche LS, Tsirka SE, Maletic-Savatic M (2010) Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis. Cell Stem Cell, 7:483-95
16. Talos F, Abraham A, Vaseva A, Holembowski L, Tsirka SE, Scheel A, Bode D, Dobbelstein M, Bruck W, Moll UM (2010) p73 is an Essential Regulator of Neural Stem Cell Maintenance in Embryonal and Adult CNS Neurogenesis. Cell Death Diff, 17:1816-29
17. Zhai H, Heppner FL, Tsirka SE (2011). Microglia/Macrophages Promote Glioma Progression, Glia. 59:472-85. PMCID: PMC3080032
18. Yao Y and Tsirka, SE (2011) Truncation of Monocyte Chemoattractant Protein-1 by Plasmin Promotes Blood-Brain Barrier Disruption. J Cell Sci. 124:1486-95. PMCID: PMC3078815
19. Yao Y and Tsirka, SE (2011) Mouse MCP1 C-terminus inhibits human MCP1-induced chemotaxis and BBB compromise. J Neurochem, in press. NIHMSID #299839
20. Zhai H, Acharya S, Gravanis I, Mehmood S, Seidman R, Shroyer K, Hajjar KA, and Tsirka SE (2011) Annexin A2 Promotes Glioma Cell Invasion and Tumor Progression. J. Neurosci., in press.
Dr Kyungmin Ji, postdoc (email@example.com)
Zhen Gao, Graduate student (firstname.lastname@example.org)
Jillian Cypser, Graduate student (email@example.com)
Luisa Torres, Graduate student (firstname.lastname@example.org)
Robert Bronstein, Graduate student (email@example.com)
|Research Interests||Publications||Current Lab Members|
Neuronal-microglial interactions in the physiology and pathology of the central nervous system
Proteases modulate neuronal cell structure and viability in the CNS.
Tissue plasminogen activator (tPA) is an extracellular serine protease
originally studied for its ability to dissolve thrombotic clots in the
vascular system. tPA initiates a proteolytic cascade that ultimately
mediates the degeneration of neuronal cells after experimental injury in
the hippocampus. Mice lacking tPA are resistant to excitotoxin-induced
neuronal death, and wild-type mice can be made resistant through the
administration of tPA inhibitors. Similar resistance is observed in mice
deficient for tPA's substrate, plasminogen. tPA may function under
physiological conditions to regulate neurite outgrowth. In addition, tPA
via a non-proteolytic mechanism has a second role, which is to trigger
the activation of microglial cells. Microglia are immune-competent,
macrophage-like cells that reside in the CNS and are involved in
neurodegeneration under conditions of excessive stimulation, or are
hypothesized to affect neuronal structural changes occurring in response
to neuronal activity. Our research interests concern the communication,
signaling events and cell-cell interactions between neurons and
microglia subsequent to normal or exaggerated stimulation of the central
nervous system that lead to reorganization of neuronal connections in
the brain or neuronal cell death.
- Gravanis I, Tsirka SE. (2008) Tissue-type plasminogen activator as a therapeutic target in stroke. Expert Opin Ther Targets. 12(2):159-70.
- Nolin WB, Emmetsberger J, Bukhari N, Zhang Y, Levine JM, Tsirka SE.(2008) tPA-mediated generation of plasmin is catalyzed by the proteoglycan NG2. Glia. 56(2):177-89
- Mirrione MM, Schiffer WK, Fowler JS, Alexoff DL, Dewey SL, Tsirka SE. (2007)A novel approach for imaging brain-behavior relationships in mice reveals unexpected metabolic patterns during seizures in the absence of tissue plasminogen activator. Neuroimage. 38(1):34-42.
- Bhasin M, Wu M, Tsirka SE. (2007) Modulation of microglial/macrophage activation by macrophage inhibitory factor (TKP) or tuftsin (TKPR) attenuates the disease course of experimental autoimmune encephalomyelitis. BMC Immunol. 8:10
- Thiex R, Tsirka SE. (2007) Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus. 22(5):E6.
- Parathath SR, Gravanis I, Tsirka SE. (2007) Nitric oxide synthase isoforms undertake unique roles during excitotoxicity. Stroke. 38(6):1938-45.
- Sheehan JJ, Zhou C, Gravanis I, Rogove AD, Wu YP, Bogenhagen DF, Tsirka SE.(2007) Proteolytic activation of monocyte chemoattractant protein-1 by plasmin underlies excitotoxic neurodegeneration in mice. J Neurosci. 27(7):1738-45.
- Parathath SR, Parathath S, Tsirka SE. (2006) Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice. J Cell Sci. 119:339-49.
- Mirrione MM, Schiffer WK, Siddiq M, Dewey SL, Tsirka SE (2006). PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy.59 119-21. PDF
- Parathath SR, Parathath S, Tsirka SE (2006). Nitric oxide mediates neurodegeneration and breakdown of the blood-brain barrier in tPA-dependent excitotoxic injury in mice.J Cell Sci. 119 339-49. PDF
- Gravanis I, Tsirka SE (2005). Tissue plasminogen activator and glial function.GLIA 49 177-83. PDF
- Wang J, Tsirka SE (2005). Tuftsin fragment 1-3 is beneficial when delivered after the induction of intracerebral hemorrhage. Stroke 36 613-8. PDF
- Zhang Y, Kanaho Y, Frohman MA, Tsirka SE (2005). Phospholipase D1-promoted release of tissue plasminogen activator facilitates neurite outgrowth.J Neurosci. 25 1797-805. PDF
- Wang J, Tsirka SE (2005). Neuroprotection by inhibition of matrix metalloproteinases in a mouse model of intracerebral haemorrhage. Brain 128 1622-33. PDF
- Zhang Y, Pothakos K, Tsirka SA (2005). Extracellular proteases: biological and behavioral roles in the mammalian central nervous system.Curr Top Dev Biol. 66 161-88.
- Sheehan JJ, Tsirka SE (2005). Fibrin-modifying serine proteases thrombin, tPA, and plasmin in ischemic stroke: a review.GLIA 50 340-50. PDF
- Xanthopoulos K, Paspaltsis I, Apostolidou V, Petrakis S, Siao CJ, Kalpatsanidis A, Grigoriadis N, Tsaftaris A, Tsirka SE, Sklaviadis T (2005). Tissue plasminogen activator in brain tissues infected with transmissible spongiform encephalopathies. PDF
- Wang J, Tsirka SE (2005). Contribution of extracellular proteolysis and microglia to intracerebral hemorrhage. Neurocrit Care 3 77-85.
- Zhang Y, Huang P, Du G, Kanaho Y, Frohman MA, Tsirka SE (2004). Increased expression of two phospholipase D isoforms during experimentally induced hippocampal mossy fiber outgrowth.GLIA 46 74-83. PDF
- Siddiq MM, Tsirka SE (2004). Modulation of zinc toxicity by tissue plasminogen activator.Mol Cell Neurosci 25 162-71. PDF
- Thiex R, Mayfrank L, Rohde V, Gilsbach JM, Tsirka SA (2004). The role of endogenous versus exogenous tPA on edema formation in murine ICH. Exp Neurol 189 25-32. PDF
- Wang J, Rogove AD, Tsirka AE, Tsirka SE (2003). Protective role of tuftsin fragment 1-3 in an animal model of intracerebral hemorrhage.54 655-64. PDF
- C-J Siao, S.R. Fernandez, S.E. Tsirka. (2003) Cell type-specific roles for tissue plasminogen activator released by neurons of microglia after excitotoxic injury. J.Neurosci. 23: 3234-3242. PDF
- J.A. Indyk, Z.L. Chen, S.E. Tsirka, and S. Strickland. (2003) Laminin chain expression suggests that laminin-10 is a major isoform in the mouse hippocampus and is degraded by the tissue plasminogen activator/plasmin protease cascade during excitotoxic injury. Neurosci. 116:359-371 PDF
- W. Lu, M. Bhasin and S.E. Tsirka. (2002) Involvement of tissue plasminogen activator in both onset and effector phases of experimental allergic encephalomyelitis. J. Neurosci. 22: 10781-10789.PDF
A. Rogove, W. Lu, SE Tsirka. (2002) Microglial activation and recruitment, but not proliferation, suffice to mediate neurodegeneration. Cell Death and Differentiation, 9: 801-806. PDF
- C-J Siao and S.E. Tsirka. (2002) Tissue plasminogen activator mediates microglial activation via its finger domain through annexin II. J Neurosci, 22: 3352-3358 PDF
- C-J Siao and S.E. Tsirka.(2002) Extracellular proteases and neuronal cell death. Mol. Cell. Bio.48: 151-161.
- S.E. Tsirka. (2002) Tissue plasminogen activator as a modulator of neuronal survival and function. Biochem. Soc. Trans.30: 222-225. PDF
- W. Lu and S.E. Tsirka. (2002) Partial rescue of neural apoptosis in the lurcher mutant mouse through elimination of tissue plasminogen activator, Development, 129: 2043-2050. PDF
- T. Mori, X. Wang, A.E. Kline, C-J. Siao, C.E. Dixon, S.E. Tsirka, and E.H. Lo. (2001) Reduced cortical injury and brain edema in tissue plasminogen activator knockout mice after brain trauma. NeuroReport12: 4117-4120.
- Wu, Y.-P., Siao, C.-J., Lu, W., Sung, T.-C., Frohman, M.A., Milev, P., Bugge, T.H., Degen, J.L., Levine, J.M., Margolis, R.U., and Tsirka, S.E. (2000). The tPA/plasmin extracellular proteolytic system regulates hippocampal mossy fiber reorganization through a novel proteoglycan substrate. J. Cell Biol. 148:1295-1304. PDF
- Rogove, A.D. , Siao, C.-J., Keyt, B., Strickland, S., and Tsirka, S.E. (1999). Activation of microglia in the mouse hippocampus reveals a non-proteolytic function for tissue plasminogen activator. J. Cell Sci. 112: 4007-4016.PDF
- Wang, Y.F., Tsirka, S.E., Strickland, S., Stieg, P.E., Soriano, S.G., and S.A. Lipton. (1998). Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nature Med.4: 228-232.
- Rogove, A.D. and Tsirka, S.E. (1998). Neurotoxic responses by microglia elicited by excitotoxic injury in the mouse hippocampus. Curr. Biol. 8: 19-25.PDF
- Tsirka, S.E. (1997). Clinical implications of the involvement of tPA in neuronal cell death. J. Mol. Med. 75: 341-347.PDF
- Tsirka, S.E., Rogove, A.D., Bugge, T.H., Degen, J.L., and Strickland, S. (1997). An extracellular proteolytic cascade promotes neuronal degeneration in the mouse hippocampus. J. Neurosci.17 : 543-552. PDF
- Tsirka, S.E., Rogove, A.D., and Strickland, S. (1996). Tissue plasminogen activator and neuronal cell death. Nature 384:123-124.
- West MF, Verrotti AC, Salles FJ, Tsirka SE, Strickland S (1996). Isolation and characterization of two novel, cytoplasmically polyadenylated, oocyte-specific, mouse maternal RNAs.Dev Biol. 175 132-41.PDF
- Gualandris, A., Jones, T., Strickland, S., and Tsirka, S.E. (1996). Membrane depolarization induces the Ca2+-dependent release of tissue plasminogen activator. J. Neurosci. 16: 2220-2225. PDF
- Tsirka, S.E., Gualandris, A., Amaral, D.G., and Strickland, S. (1995). Excitotoxin-induced neuronal degeneration and seizure are mediated by tissue-type plasminogen activator. Nature 377: 340-344.
- Carroll PM, Tsirka SE, Richards WG, Frohman MA, Strickland S (1994). The mouse tissue plasminogen activator gene 5' flanking region directs appropriate expression in development and a seizure-enhanced response in the CNS.120 3173-83. PDF
- Tsirka SE, Turck CW, Coffino P (1993). Multiple active conformers of mouse ornithine decarboxylase. Biochem J. 293 (P 289-95). PDF
Professor, Pharmacological Sciences
Ph.D.: University of Thessaloniki, Greece,
Postdoctorals: University of California, San Francisco and Stony Brook University
Department of Pharmacological Sciences BST8, Rm 192 Stony Brook University
Stony Brook, NY 11794-8651