Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy
Interplay of IKK/NF-κB signaling in macrophages and myofibers promotes muscle degeneration in Duchenne muscular dystrophy
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DOI：
10.1172/jci30556
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发表时间：
2007-04-01
影响因子：
15.9
通讯作者：
Guttridge, Denis C.
中科院分区：
文献类型：
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作者：
Acharyya, Swarnali;Villalta, S. Armando;Guttridge, Denis C.
杜氏肌营养不良症（DMD）是一种与肌营养不良蛋白缺乏相关的致死性X连锁疾病，其导致慢性炎症和严重的骨骼肌变性。在DMD小鼠模型和患者中，我们发现I κ B激酶/NF-κ B（IKK/NF-κ B）信号在免疫细胞和再生肌纤维中持续升高。去除NF-κ B的p65亚基的1个等位基因足以改善mdx小鼠（DMD模型）的病理学。此外，mdx小鼠中IKK β的条件性缺失阐明了NF-κ B在活化的巨噬细胞中的功能是促进炎症和肌肉坏死，在骨骼肌纤维中的功能是通过抑制肌肉祖细胞来限制再生。此外，IKK的特异性药理学抑制导致mdx小鼠的病理学和肌肉功能改善。总的来说，这些结果强调了NF-κ B在肌营养不良症进展中的关键作用，并表明IKK/NF-κ B信号通路作为DMD的潜在治疗靶点。
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models and patients, we find that I kappa B kinase/NF-kappa B (IKK/NF-kappa B) signaling is persistently elevated in immune cells and regenerative muscle fibers. Ablation of 1 allele of the p65 subunit of NF-kappa B was sufficient to improve pathology in mdx mice, a model of DMD. In addition, conditional deletion of IKK beta in mdx mice elucidated that NF-kappa B functions in activated macrophages to promote inflammation and muscle necrosis and in skeletal muscle fibers to limit regeneration through the inhibition of muscle progenitor cells. Furthermore, specific pharmacological inhibition of IKK resulted in improved pathology and muscle function in mdx mice. Collectively, these results underscore the critical role of NF-kappa B in the progression of muscular dystrophy and suggest the IKK/NF-kappa B signaling pathway as a potential therapeutic target for DMD.