期刊
MOLECULAR BRAIN
卷 14, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13041-021-00785-8
关键词
Amyotrophic lateral sclerosis; Astrocyte; Interleukin-19; Microglia
资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan
- Ministry of Health, Labour and Welfare of Japan
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO) of Japan
- Naito Foundation
- Yokohama City University [SK2804]
Neuroinflammation in ALS is regulated by IL-19, as IL-19-deficient mice showed improved motor function and altered expression of both neurotoxic and neuroprotective factors. Inhibition of IL-19 signaling could potentially alleviate symptoms of ALS.
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-alpha (TNF-alpha), IL-1 beta, glial cell line-derived neurotrophic factor (GDNF), and transforming growth factor beta 1, in lumbar spinal cord. Primary microglia and astrocytes from IL-19(-/-)/SOD1(G93A) Tg mice expressed higher levels of TNF-alpha, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.
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