Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.

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 i...

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Autores principales:	Arseny Finkelstein, Gilad Kunis, Akop Seksenyan, Ayal Ronen, Tamara Berkutzki, David Azoulay, Maya Koronyo-Hamaoui, Michal Schwartz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/75f41992ebaf4f08877705a42d21278a
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spelling	oai:doaj.org-article:75f41992ebaf4f08877705a42d21278a2021-11-18T06:48:52ZAbnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.1932-620310.1371/journal.pone.0022374https://doaj.org/article/75f41992ebaf4f08877705a42d21278a2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21829620/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Amyotrophic 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.Arseny FinkelsteinGilad KunisAkop SeksenyanAyal RonenTamara BerkutzkiDavid AzoulayMaya Koronyo-HamaouiMichal SchwartzPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 8, p e22374 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Arseny Finkelstein Gilad Kunis Akop Seksenyan Ayal Ronen Tamara Berkutzki David Azoulay Maya Koronyo-Hamaoui Michal Schwartz Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
description	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.
format	article
author	Arseny Finkelstein Gilad Kunis Akop Seksenyan Ayal Ronen Tamara Berkutzki David Azoulay Maya Koronyo-Hamaoui Michal Schwartz
author_facet	Arseny Finkelstein Gilad Kunis Akop Seksenyan Ayal Ronen Tamara Berkutzki David Azoulay Maya Koronyo-Hamaoui Michal Schwartz
author_sort	Arseny Finkelstein
title	Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
title_short	Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
title_full	Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
title_fullStr	Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
title_full_unstemmed	Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.
title_sort	abnormal changes in nkt cells, the igf-1 axis, and liver pathology in an animal model of als.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/75f41992ebaf4f08877705a42d21278a
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Abnormal changes in NKT cells, the IGF-1 axis, and liver pathology in an animal model of ALS.

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