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Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage

Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-...

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Autores principales: Zhang, Zhiying, Li, Yinuo, Shi, Juyuan, Zhu, Li, Dai, Yinming, Fu, Peiji, Liu, Simon, Hong, Michael, Zhang, Jiewen, Wang, Jian, Jiang, Chao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: JKL International LLC 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187706/
https://www.ncbi.nlm.nih.gov/pubmed/37191423
http://dx.doi.org/10.14336/AD.2022.1102
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author Zhang, Zhiying
Li, Yinuo
Shi, Juyuan
Zhu, Li
Dai, Yinming
Fu, Peiji
Liu, Simon
Hong, Michael
Zhang, Jiewen
Wang, Jian
Jiang, Chao
author_facet Zhang, Zhiying
Li, Yinuo
Shi, Juyuan
Zhu, Li
Dai, Yinming
Fu, Peiji
Liu, Simon
Hong, Michael
Zhang, Jiewen
Wang, Jian
Jiang, Chao
author_sort Zhang, Zhiying
collection PubMed
description Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy.
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spelling pubmed-101877062023-06-01 Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage Zhang, Zhiying Li, Yinuo Shi, Juyuan Zhu, Li Dai, Yinming Fu, Peiji Liu, Simon Hong, Michael Zhang, Jiewen Wang, Jian Jiang, Chao Aging Dis Original Article Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy. JKL International LLC 2023-06-01 /pmc/articles/PMC10187706/ /pubmed/37191423 http://dx.doi.org/10.14336/AD.2022.1102 Text en Copyright: © 2023 Zhang et al. https://creativecommons.org/licenses/by/2.0/this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
spellingShingle Original Article
Zhang, Zhiying
Li, Yinuo
Shi, Juyuan
Zhu, Li
Dai, Yinming
Fu, Peiji
Liu, Simon
Hong, Michael
Zhang, Jiewen
Wang, Jian
Jiang, Chao
Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title_full Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title_fullStr Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title_full_unstemmed Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title_short Lymphocyte-Related Immunomodulatory Therapy with Siponimod (BAF-312) Improves Outcomes in Mice with Acute Intracerebral Hemorrhage
title_sort lymphocyte-related immunomodulatory therapy with siponimod (baf-312) improves outcomes in mice with acute intracerebral hemorrhage
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10187706/
https://www.ncbi.nlm.nih.gov/pubmed/37191423
http://dx.doi.org/10.14336/AD.2022.1102
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