PDF(Pubmed)
Abstract：
Regulation of neuroinflammation is critical for maintaining central nervous system (CNS) homeostasis and holds therapeutic promise in autoimmune diseases such as multiple sclerosis (MS). Previous studies have highlighted the significance of selective innate signaling in triggering anti-inflammatory mechanisms, which play a protective role in an MS-like disease, experimental autoimmune encephalomyelitis (EAE). However, the individual intra-CNS administration of specific innate receptor ligands or agonists, such as for toll-like receptor 7 (TLR7) and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2), failed to elicit the desired anti-inflammatory response in EAE. In this study, we investigated the potential synergistic effect of targeting both TLR7 and NOD2 simultaneously to prevent EAE progression. Our findings demonstrate that simultaneous intrathecal administration of NOD2- and TLR7-agonists led to synergistic induction of Type I IFN (IFN I) and effectively suppressed EAE in an IFN I-dependent manner. Suppression of EAE was correlated with a significant decrease in the infiltration of monocytes, granulocytes, and natural killer cells, reduced demyelination, and downregulation of IL-1β, CCL2, and IFNγ gene expression in the spinal cord. These results underscore the therapeutic promise of concurrently targeting the TLR7 and NOD2 pathways in alleviating neuroinflammation associated with MS, paving the way for novel and more efficacious treatment strategies.
摘要：
神经炎症的调节对于维持中枢神经系统（CNS）稳态至关重要，并且在诸如多发性硬化症（MS）的自身免疫性疾病中具有治疗前景。以前的研究已经强调了选择性先天信号在触发抗炎机制中的意义。在MS样疾病中起保护作用，实验性自身免疫性脑脊髓炎（EAE）。然而,个别中枢神经系统内给予特定的先天受体配体或激动剂，例如Toll样受体7（TLR7）和含核苷酸结合寡聚化结构域的蛋白2（NOD2），未能在EAE中引发所需的抗炎反应。在这项研究中,我们研究了同时靶向TLR7和NOD2预防EAE进展的潜在协同作用.我们的发现表明，鞘内同时注射NOD2-和TLR7激动剂可协同诱导I型IFN（IFNI），并以IFNI依赖性方式有效抑制EAE。EAE的抑制与单核细胞浸润的显著减少相关,粒细胞,和自然杀伤细胞，减少脱髓鞘,和IL-1β的下调，CCL2和IFNγ基因在脊髓中的表达。这些结果强调了同时靶向TLR7和NOD2途径缓解与MS相关的神经炎症的治疗前景。为新颖和更有效的治疗策略铺平了道路。
