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Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease with few therapeutic options. However, the immune system, including natural killer (NK) cells, is linked to ALS progression and may constitute a viable therapeutic ALS target. Tofacitinib is an FDA-approved immuno...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859451/ https://www.ncbi.nlm.nih.gov/pubmed/35197969 http://dx.doi.org/10.3389/fimmu.2022.773288 |
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author | Figueroa-Romero, Claudia Monteagudo, Alina Murdock, Benjamin J. Famie, Joshua P. Webber-Davis, Ian F. Piecuch, Caroline E. Teener, Samuel J. Pacut, Crystal Goutman, Stephen A. Feldman, Eva L. |
author_facet | Figueroa-Romero, Claudia Monteagudo, Alina Murdock, Benjamin J. Famie, Joshua P. Webber-Davis, Ian F. Piecuch, Caroline E. Teener, Samuel J. Pacut, Crystal Goutman, Stephen A. Feldman, Eva L. |
author_sort | Figueroa-Romero, Claudia |
collection | PubMed |
description | Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease with few therapeutic options. However, the immune system, including natural killer (NK) cells, is linked to ALS progression and may constitute a viable therapeutic ALS target. Tofacitinib is an FDA-approved immunomodulating small molecule which suppresses immune cell function by blocking proinflammatory cytokine signaling. This includes the cytokine IL-15 which is the primary cytokine associated with NK cell function and proliferation. However, the impact of tofacitinib on NK activation and cytotoxicity has not been thoroughly investigated, particularly in ALS. We therefore tested the ability of tofacitinib to suppress cytotoxicity and cytokine production in an NK cell line and in primary NK cells derived from control and ALS participants. We also investigated whether tofacitinib protected ALS neurons from NK cell cytotoxicity. Finally, we conducted a comprehensive pharmacokinetic study of tofacitinib in mice and tested the feasibility of administration formulated in chow. Success was assessed through the impact of tofacitinib on peripheral NK cell levels in mice. We found tofacitinib suppressed IL-15-induced activation as measured by STAT1 phosphorylation, cytotoxicity, pro-inflammatory gene expression, and pro-inflammatory cytokine secretion in both an NK cell line and primary NK cells. Furthermore, tofacitinib protected ALS neurons from NK cell-mediated cytotoxicity. In mice, we found tofacitinib bioavailability was 37% in both male and female mice; using these data we formulated mouse containing low and high doses of tofacitinib and found that the drug suppressed peripheral NK cell levels in a dose-dependent manner. These results demonstrate that tofacitinib can suppress NK cell function and may be a viable therapeutic strategy for ALS. |
format | Online Article Text |
id | pubmed-8859451 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-88594512022-02-22 Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis Figueroa-Romero, Claudia Monteagudo, Alina Murdock, Benjamin J. Famie, Joshua P. Webber-Davis, Ian F. Piecuch, Caroline E. Teener, Samuel J. Pacut, Crystal Goutman, Stephen A. Feldman, Eva L. Front Immunol Immunology Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative disease with few therapeutic options. However, the immune system, including natural killer (NK) cells, is linked to ALS progression and may constitute a viable therapeutic ALS target. Tofacitinib is an FDA-approved immunomodulating small molecule which suppresses immune cell function by blocking proinflammatory cytokine signaling. This includes the cytokine IL-15 which is the primary cytokine associated with NK cell function and proliferation. However, the impact of tofacitinib on NK activation and cytotoxicity has not been thoroughly investigated, particularly in ALS. We therefore tested the ability of tofacitinib to suppress cytotoxicity and cytokine production in an NK cell line and in primary NK cells derived from control and ALS participants. We also investigated whether tofacitinib protected ALS neurons from NK cell cytotoxicity. Finally, we conducted a comprehensive pharmacokinetic study of tofacitinib in mice and tested the feasibility of administration formulated in chow. Success was assessed through the impact of tofacitinib on peripheral NK cell levels in mice. We found tofacitinib suppressed IL-15-induced activation as measured by STAT1 phosphorylation, cytotoxicity, pro-inflammatory gene expression, and pro-inflammatory cytokine secretion in both an NK cell line and primary NK cells. Furthermore, tofacitinib protected ALS neurons from NK cell-mediated cytotoxicity. In mice, we found tofacitinib bioavailability was 37% in both male and female mice; using these data we formulated mouse containing low and high doses of tofacitinib and found that the drug suppressed peripheral NK cell levels in a dose-dependent manner. These results demonstrate that tofacitinib can suppress NK cell function and may be a viable therapeutic strategy for ALS. Frontiers Media S.A. 2022-02-07 /pmc/articles/PMC8859451/ /pubmed/35197969 http://dx.doi.org/10.3389/fimmu.2022.773288 Text en Copyright © 2022 Figueroa-Romero, Monteagudo, Murdock, Famie, Webber-Davis, Piecuch, Teener, Pacut, Goutman and Feldman https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Figueroa-Romero, Claudia Monteagudo, Alina Murdock, Benjamin J. Famie, Joshua P. Webber-Davis, Ian F. Piecuch, Caroline E. Teener, Samuel J. Pacut, Crystal Goutman, Stephen A. Feldman, Eva L. Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title | Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title_full | Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title_fullStr | Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title_full_unstemmed | Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title_short | Tofacitinib Suppresses Natural Killer Cells In Vitro and In Vivo: Implications for Amyotrophic Lateral Sclerosis |
title_sort | tofacitinib suppresses natural killer cells in vitro and in vivo: implications for amyotrophic lateral sclerosis |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8859451/ https://www.ncbi.nlm.nih.gov/pubmed/35197969 http://dx.doi.org/10.3389/fimmu.2022.773288 |
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