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Arseny Finkelstein,
Gilad Kunis, Tamara Berkutzki,
Ayal Ronen,
Amir Krivoy,
Eti Yoles,
David Last,
Yael Mardor,
Kerry Van Shura,
Emylee McFarland,
Benedict A Capacio,
Claire Eisner,
Mary Gonzales,
Danise Gregorowicz,
Arik Eisenkraft,
John H McDonough,
Michal Schwartz
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ABSTRACT: Accidental organophosphate poisoning resulting from environmental or occupational exposure, as well as the deliberate use of nerve agents on the battlefield or by terrorists, remain major threats for multi-casualty events, with no effective therapies yet available. Even transient exposure to organophosphorous compounds may lead to brain damage associated with microglial activation and to long-lasting neurological and psychological deficits. Regulation of the microglial response by adaptive immunity was previously shown to reduce the consequences of acute insult to the central nervous system (CNS). Here, we tested whether an immunization-based treatment that affects the properties of T regulatory cells (Tregs) can reduce brain damage following organophosphate intoxication, as a supplement to the standard antidotal protocol. Rats were intoxicated by acute exposure to the nerve agent soman, or the organophosphate pesticide, paraoxon, and after 24 h were treated with the immunomodulator, poly-YE. A single injection of poly-YE resulted in a significant increase in neuronal survival and tissue preservation. The beneficial effect of poly-YE treatment was associated with specific recruitment of CD4(+) T cells into the brain, reduced microglial activation, and an increase in the levels of brain derived neurotrophic factor (BDNF) in the piriform cortex. These results suggest therapeutic intervention with poly-YE as an immunomodulatory supplementary approach against consequences of organophosphate-induced brain damage.
Brain Behavior and Immunity 09/2011; 26(1):159-69. · 4.72 Impact Factor
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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4(+) T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.
PLoS ONE 01/2011; 6(8):e22374. · 4.09 Impact Factor
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Yael Pewzner-Jung,
Ori Brenner,
Svantje Braun,
Elad L Laviad,
Shifra Ben-Dor,
Ester Feldmesser,
Shirley Horn-Saban,
Daniela Amann-Zalcenstein,
Calanit Raanan, Tamara Berkutzki,
Racheli Erez-Roman,
Oshrit Ben-David,
Michal Levy,
Dorin Holzman,
Heyjung Park,
Abraham Nyska,
Alfred H Merrill,
Anthony H Futerman
[show abstract]
[hide abstract]
ABSTRACT: We have generated a mouse that cannot synthesize very long acyl chain (C22-C24) ceramides (Pewzner-Jung, Y., Park, H., Laviad, E. L., Silva, L. C., Lahiri, S., Stiban, J., Erez-Roman, R., Brugger, B., Sachsenheimer, T., Wieland, F. T., Prieto, M., Merrill, A. H., and Futerman, A. H. (2010) J. Biol. Chem. 285, 10902-10910) due to ablation of ceramide synthase 2 (CerS2). As a result, significant changes were observed in the sphingolipid profile of livers from these mice, including elevated C16-ceramide and sphinganine levels. We now examine the functional consequences of these changes. CerS2 null mice develop severe nonzonal hepatopathy from about 30 days of age, the age at which CerS2 expression peaks in wild type mice, and display increased rates of hepatocyte apoptosis and proliferation. In older mice there is extensive and pronounced hepatocellular anisocytosis with widespread formation of nodules of regenerative hepatocellular hyperplasia. Progressive hepatomegaly and noninvasive hepatocellular carcinoma are also seen from approximately 10 months of age. Even though CerS2 is found at equally high mRNA levels in kidney and liver, there are no changes in renal function and no pathological changes in the kidney. High throughput analysis of RNA expression in liver revealed up-regulation of genes associated with cell cycle regulation, protein transport, cell-cell interactions and apoptosis, and down-regulation of genes associated with intermediary metabolism, such as lipid and steroid metabolism, adipocyte signaling, and amino acid metabolism. In addition, levels of the cell cycle regulator, the cyclin dependent-kinase inhibitor p21(WAF1/CIP1), were highly elevated, which occurs by at least two mechanisms, one of which may involve p53. We propose a functional rationale for the synthesis of sphingolipids with very long acyl chains in liver homeostasis and in cell physiology.
Journal of Biological Chemistry 04/2010; 285(14):10911-23. · 4.77 Impact Factor
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Yael Pewzner-Jung,
Ori Brenner,
Svantje Braun,
Elad L. Laviad,
Shifra Ben-Dor,
Ester Feldmesser,
Shirley Horn-Saban,
Daniela Amann-Zalcenstein,
Calanit Raanan, Tamara Berkutzki,
Racheli Erez-Roman,
Oshrit Ben-David,
Michal Levy,
Dorin Holzman,
Hyejung Park,
Abraham Nyska,
Jr. Alfred H. Merrill,
Anthony H. Futerman
[show abstract]
[hide abstract]
ABSTRACT: We have generated a mouse that cannot synthesize very long acyl chain (C22–C24) ceramides (Pewzner-Jung, Y., Park, H., Laviad,
E. L., Silva, L. C., Lahiri, S., Stiban, J., Erez-Roman, R., Brugger, B., Sachsenheimer, T., Wieland, F. T., Prieto, M., Merrill,
A. H., and Futerman, A. H. (2010) J. Biol. Chem. 285, 10902–10910) due to ablation of ceramide synthase 2 (CerS2). As a result, significant changes were observed in the sphingolipid profile
of livers from these mice, including elevated C16-ceramide and sphinganine levels. We now examine the functional consequences
of these changes. CerS2 null mice develop severe nonzonal hepatopathy from about 30 days of age, the age at which CerS2 expression
peaks in wild type mice, and display increased rates of hepatocyte apoptosis and proliferation. In older mice there is extensive
and pronounced hepatocellular anisocytosis with widespread formation of nodules of regenerative hepatocellular hyperplasia.
Progressive hepatomegaly and noninvasive hepatocellular carcinoma are also seen from ∼10 months of age. Even though CerS2
is found at equally high mRNA levels in kidney and liver, there are no changes in renal function and no pathological changes
in the kidney. High throughput analysis of RNA expression in liver revealed up-regulation of genes associated with cell cycle
regulation, protein transport, cell-cell interactions and apoptosis, and down-regulation of genes associated with intermediary
metabolism, such as lipid and steroid metabolism, adipocyte signaling, and amino acid metabolism. In addition, levels of the
cell cycle regulator, the cyclin dependent-kinase inhibitor p21WAF1/CIP1, were highly elevated, which occurs by at least two mechanisms, one of which may involve p53. We propose a functional rationale
for the synthesis of sphingolipids with very long acyl chains in liver homeostasis and in cell physiology.
Journal of Biological Chemistry 04/2010; 285(14):10911-10923. · 4.77 Impact Factor
