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

Hiroyasu Komiya,Fumiaki Tanaka,Kosuke Suzuki,Yasu-Taka Azuma,Akihiro Ogasawara,Keita Takahashi,Hideyuki Takeuchi,Yuki Ogawa,Hiroshi Doi

doi:10.1186/s13041-021-00785-8

Abstract

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 (SOD1G93A Tg mice). We generated IL-19–deficient SOD1G93A Tg (IL-19−/−/SOD1G93A Tg) mice by crossing SOD1G93A 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 SOD1G93A Tg mice and IL-19−/−/SOD1G93A Tg mice. Expression of IL-19 in primary microglia and lumbar spinal cord was higher in SOD1G93A Tg mice than in wild-type mice. Unexpectedly, IL-19−/−/SOD1G93A Tg mice exhibited significant improvement of motor function. Ablation of IL-19 in SOD1G93A 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−/−/SOD1G93A Tg mice expressed higher levels of TNF-α, resulting in release of GDNF from astrocytes. Inhibition of IL-19 signaling may alleviate ALS symptoms.

Highlights

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by motor neuron degeneration, which leads to progressive muscle weakness, amyotrophy, and death from respiratory paralysis within 3–5 years from onset [1]
IL‐19 is upregulated in primary microglia and lumbar spinal cord of S OD1G93A Tg mice First, we examined IL-19 expression levels in primary microglia and lumbar spinal cords of wild-type and SOD1G93A Tg mice. quantitative reverse transcription PCR (qPCR) analyses revealed that IL-19 expression in primary microglia was significantly higher in SOD1G93A Tg mice than in wild-type mice (Fig. 1a). SOD1G93A Tg mice exhibited elevated expression of IL-19 in the lumbar spinal cords as the disease progressed (Fig. 1b)
Ablation of IL‐19 upregulates both neurotoxic and neuroprotective factors in lumbar spinal cord of SOD1G93A Tg mice we evaluated the expression levels of neurotoxic and neuroprotective factors in the lumbar spinal cords of SOD1G93A Tg and IL-19−/−/SOD1G93A Tg mice at the late stage (20 weeks) when motor function began to show a significant difference. qPCR analyses for pro-inflammatory factors revealed that expression levels of tumor necrosis factor-α (TNF-α) and Interleukin-1 beta (IL-1β) were significantly upregulated in IL-19−/−/ SOD1G93A Tg mice compared to SOD1G93A Tg mice (Fig. 5a–d)

Summary

Introduction

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by motor neuron degeneration, which leads to progressive muscle weakness, amyotrophy, and death from respiratory paralysis within 3–5 years from onset [1]. ALS is thought to be caused by a multi-factorial mechanism, including glial neuroinflammation, oxidative stress, glutamate-mediated. IL-19 was grouped into the IL-20 subfamily, which includes IL-20, IL-22, and IL-24, because these cytokines share common receptor. IL-19 is an anti-inflammatory cytokine, produced by activated microglia and macrophages, that acts as a negative-feedback regulator to limit pro-inflammatory responses by these cells in an autocrine and paracrine manner [9, 10]. In regard to its anti-inflammatory role, IL-19 inhibits the symptoms of animal models of inflammatory bowel disease [10, 12], suppresses hapten-dependent skin inflammation in contact hypersensitivity [13], decreases brain infarction area in a mouse model of cerebral ischemia [14], and improves locomotor function in a mouse model of spinal cord injury [15]. IL-19 acts as a proinflammatory cytokine in T helper 2 cell (Th2)-mediated diseases such as asthma and rheumatoid arthritis. IL-19 exerts either anti-inflammatory or proinflammatory effects in accordance with immunological conditions

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