Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica, 1, 00133, Rome, Italy.
Institute of Translational Pharmacology, CNR, 00133, Rome, Italy.
J Neuroinflammation. 2021 Jun 12;18(1):132. doi: 10.1186/s12974-021-02184-1.
An increasing number of studies evidences that amyotrophic lateral sclerosis (ALS) is characterized by extensive alterations in different cell types and in different regions besides the CNS. We previously reported the upregulation in ALS models of a gene called fibroblast-specific protein-1 or S100A4, recognized as a pro-inflammatory and profibrotic factor. Since inflammation and fibrosis are often mutual-sustaining events that contribute to establish a hostile environment for organ functions, the comprehension of the elements responsible for these interconnected pathways is crucial to disclose novel aspects involved in ALS pathology.
Here, we employed fibroblasts derived from ALS patients harboring the C9orf72 hexanucleotide repeat expansion and ALS patients with no mutations in known ALS-associated genes and we downregulated S100A4 using siRNA or the S100A4 transcriptional inhibitor niclosamide. Mice overexpressing human FUS were adopted to assess the effects of niclosamide in vivo on ALS pathology.
We demonstrated that S100A4 underlies impaired autophagy and a profibrotic phenotype, which characterize ALS fibroblasts. Indeed, its inhibition reduces inflammatory, autophagic, and profibrotic pathways in ALS fibroblasts, and interferes with different markers known as pathogenic in the disease, such as mTOR, SQSTM1/p62, STAT3, α-SMA, and NF-κB. Importantly, niclosamide in vivo treatment of ALS-FUS mice reduces the expression of S100A4, α-SMA, and PDGFRβ in the spinal cord, as well as gliosis in central and peripheral nervous tissues, together with axonal impairment and displays beneficial effects on muscle atrophy, by promoting muscle regeneration and reducing fibrosis.
Our findings show that S100A4 has a role in ALS-related mechanisms, and that drugs such as niclosamide which are able to target inflammatory and fibrotic pathways could represent promising pharmacological tools for ALS.
越来越多的研究证据表明，肌萎缩侧索硬化症（ALS）除中枢神经系统外，还以不同细胞类型和不同区域的广泛改变为特征。我们之前报道过，在 ALS 模型中，一种称为成纤维细胞特异性蛋白 1 或 S100A4 的基因上调，该基因被认为是一种促炎和促纤维化因子。由于炎症和纤维化通常是相互维持的事件，有助于为器官功能建立一个敌对的环境，因此理解导致这些相互关联途径的因素对于揭示 ALS 病理学中涉及的新方面至关重要。
在这里，我们使用携带 C9orf72 六核苷酸重复扩展的 ALS 患者来源的成纤维细胞和无已知 ALS 相关基因突变的 ALS 患者的成纤维细胞，并使用 siRNA 或 S100A4 转录抑制剂尼洛酰胺下调 S100A4。采用过表达人 FUS 的小鼠来评估尼洛酰胺在体内对 ALS 病理学的影响。
我们证明了 S100A4 是 ALS 成纤维细胞中受损自噬和促纤维化表型的基础。事实上，它的抑制减少了 ALS 成纤维细胞中的炎症、自噬和促纤维化途径，并干扰了不同的已知作为疾病致病的标志物，如 mTOR、SQSTM1/p62、STAT3、α-SMA 和 NF-κB。重要的是，尼洛酰胺在 ALS-FUS 小鼠体内的治疗降低了脊髓中 S100A4、α-SMA 和 PDGFRβ 的表达，以及中枢和外周神经组织中的神经胶质增生，同时改善了轴突损伤，并通过促进肌肉再生和减少纤维化对肌肉萎缩产生有益影响。
我们的研究结果表明，S100A4 在 ALS 相关机制中发挥作用，而尼洛酰胺等能够靶向炎症和纤维化途径的药物可能是 ALS 的有前途的药物工具。
