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Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis

Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclea...

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Autores principales: Komiya, Hiroyasu, Takeuchi, Hideyuki, Ogawa, Yuki, Suzuki, Kosuke, Ogasawara, Akihiro, Takahashi, Keita, Azuma, Yasu-Taka, Doi, Hiroshi, Tanaka, Fumiaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086093/
https://www.ncbi.nlm.nih.gov/pubmed/33931083
http://dx.doi.org/10.1186/s13041-021-00785-8
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author Komiya, Hiroyasu
Takeuchi, Hideyuki
Ogawa, Yuki
Suzuki, Kosuke
Ogasawara, Akihiro
Takahashi, Keita
Azuma, Yasu-Taka
Doi, Hiroshi
Tanaka, Fumiaki
author_facet Komiya, Hiroyasu
Takeuchi, Hideyuki
Ogawa, Yuki
Suzuki, Kosuke
Ogasawara, Akihiro
Takahashi, Keita
Azuma, Yasu-Taka
Doi, Hiroshi
Tanaka, Fumiaki
author_sort Komiya, Hiroyasu
collection PubMed
description Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1(G93A) Tg mice). We generated IL-19–deficient SOD1(G93A) Tg (IL-19(−/−)/SOD1(G93A) Tg) mice by crossing SOD1(G93A) Tg mice with IL-19(−/−) mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1(G93A) Tg mice and IL-19(−/−)/SOD1(G93A) Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1(G93A) Tg mice than in wild-type mice. Unexpectedly, IL-19(−/−)/SOD1(G93A) Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1(G93A) Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line–derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19(−/−)/SOD1(G93A) Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.
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spelling pubmed-80860932021-04-30 Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis Komiya, Hiroyasu Takeuchi, Hideyuki Ogawa, Yuki Suzuki, Kosuke Ogasawara, Akihiro Takahashi, Keita Azuma, Yasu-Taka Doi, Hiroshi Tanaka, Fumiaki Mol Brain Research Neuroinflammation by activated microglia and astrocytes plays a critical role in progression of amyotrophic lateral sclerosis (ALS). Interleukin-19 (IL-19) is a negative-feedback regulator that limits pro-inflammatory responses of microglia in an autocrine and paracrine manner, but it remains unclear how IL-19 contributes to ALS pathogenesis. We investigated the role of IL-19 in ALS using transgenic mice carrying human superoxide dismutase 1 with the G93A mutation (SOD1(G93A) Tg mice). We generated IL-19–deficient SOD1(G93A) Tg (IL-19(−/−)/SOD1(G93A) Tg) mice by crossing SOD1(G93A) Tg mice with IL-19(−/−) mice, and then evaluated disease progression, motor function, survival rate, and pathological and biochemical alternations in the resultant mice. In addition, we assessed the effect of IL-19 on glial cells using primary microglia and astrocyte cultures from the embryonic brains of SOD1(G93A) Tg mice and IL-19(−/−)/SOD1(G93A) Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1(G93A) Tg mice than in wild-type mice. Unexpectedly, IL-19(−/−)/SOD1(G93A) Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1(G93A) Tg mice increased expression of both neurotoxic and neuroprotective factors, including tumor necrosis factor-α (TNF-α), IL-1β, glial cell line–derived neurotrophic factor (GDNF), and transforming growth factor β1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19(−/−)/SOD1(G93A) Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms. BioMed Central 2021-04-30 /pmc/articles/PMC8086093/ /pubmed/33931083 http://dx.doi.org/10.1186/s13041-021-00785-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Komiya, Hiroyasu
Takeuchi, Hideyuki
Ogawa, Yuki
Suzuki, Kosuke
Ogasawara, Akihiro
Takahashi, Keita
Azuma, Yasu-Taka
Doi, Hiroshi
Tanaka, Fumiaki
Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title_full Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title_fullStr Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title_full_unstemmed Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title_short Ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
title_sort ablation of interleukin-19 improves motor function in a mouse model of amyotrophic lateral sclerosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086093/
https://www.ncbi.nlm.nih.gov/pubmed/33931083
http://dx.doi.org/10.1186/s13041-021-00785-8
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