Modulation of Ryanodine Receptors Activity Alters the Course of Experimental Autoimmune Encephalomyelitis in Mice.
Modulation of Ryanodine Receptors Activity Alters the Course of Experimental Autoimmune Encephalomyelitis in Mice.
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DOI：
10.3389/fphys.2021.770820
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发表时间：
2021
影响因子：
4
通讯作者：
Fomina AF
中科院分区：
文献类型：
--
作者：
Osipchuk NC;Soulika AM;Fomina AF
Ryanodine受体(RyRs)是细胞内的钙释放通道，表达于T淋巴细胞和其他类型的免疫细胞。RyRs的调节已被证明在体外影响T细胞功能，在体内影响免疫反应。RyRs的调节在自身免疫性疾病发展中的作用还没有被研究过。在这里，我们研究了通过给予RyR抑制剂Dantrolene或引入功能增益RYR1-p来调节RyRs如何影响小鼠实验性自身免疫性脑脊髓炎(EAE)的临床进展，EAE是一种T细胞介导的自身免疫性神经炎性疾病。我们发现，在诱导EAE时，每天给予丹曲林5或10 mg/kg可显著减轻EAE临床症状的严重程度，并抑制脊髓的炎症。丹曲林对EAE的保护作用是可逆的。丹曲林给药引起剂量依赖性的骨骼肌无力：接受10 mg/kg剂量的小鼠出现摇摆步态，而5 mg/kg丹曲林剂量给药使四肢保持冲动值减少。携带RYR1-p.R163C功能获得突变的小鼠比野生型小鼠出现EAE临床症状更快、更严重。本研究表明RyRs在EAE的发病机制中起重要作用，提示小剂量丹曲林抑制RyRs可能对人体自身免疫和炎症具有保护作用。
Ryanodine receptors (RyRs), the intracellular Ca2+ release channels, are expressed in T lymphocytes and other types of immune cells. Modulation of RyRs has been shown to affect T cell functions in vitro and immune responses in vivo. The effects of modulation of RyRs on the development of autoimmune diseases have not been investigated. Here we studied how modulation of RyRs through administration of RyR inhibitor dantrolene or introducing a gain-of-function RYR1-p.R163C mutation affects clinical progression of experimental autoimmune encephalomyelitis (EAE) in mice, a T cell-mediated autoimmune neuroinflammatory disease. We found that daily intraperitoneal administration of 5 or 10 mg/kg dantrolene beginning at the time of EAE induction significantly reduced the severity of EAE clinical symptoms and dampened inflammation in the spinal cord. The protective effect of dantrolene on EAE was reversible. Dantrolene administration elicited dose-dependent skeletal muscle weakness: mice that received 10 mg/kg dose developed a waddling gait, while 5 mg/kg dantrolene dose administration produced a reduction in four-limb holding impulse values. Mice bearing the gain-of-function RYR1-p.R163C mutation developed the EAE clinical symptoms faster and more severely than wild-type mice. This study demonstrates that RyRs play a significant role in EAE pathogenesis and suggests that inhibition of RyRs with low doses of dantrolene may have a protective effect against autoimmunity and inflammation in humans.
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