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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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2021
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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 |
Sumario: | 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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