Toll-like receptors (TLRs) are a class of proteins that play essential roles in innate and adaptive immune responses. Recently, accumulating evidence has demonstrated that impairments in the TLR signalling pathway contribute to the development and progression of neuroimmune diseases, such as neuromyelitis optica spectrum disorder (NMOSD). However, the cellular and molecular mechanisms are still largely unknown. In this study, we report a novel variant, C52Y, of canopy FGF signalling regulator 3 (CNPY3) from patients with familial NMOSD and demonstrate that this variant shows a stronger interaction with GP96 and TLRs than with wild-type CNPY3. We find that C52Y has dominant negative effects on TLR4 surface expression. Importantly, the TLR4 surface expression level is decreased in RAW264.7 cells infected with the C52Y virus upon LPS stimulation. We further demonstrate that bone marrow-derived macrophages (BMDMs) from CNPY3^C52Y/+ transgenic mice secrete less tumour necrosis factor (TNF) and interleukin (IL)-6 than BMDMs from wild-type mice upon stimulation with LPS. These data suggest that impairment of TLR trafficking may contribute to the development of neuroimmune disorders.

Toll 样受体 (TLR) 是一类在先天性和适应性免疫反应中发挥重要作用的蛋白质。最近，越来越多的证据表明，TLR 信号通路的损伤会导致神经免疫疾病的发生和进展，例如视神经脊髓炎谱系障碍 (NMOSD)。然而，细胞和分子机制仍然很大程度上未知。在这项研究中，我们报告了来自家族性 NMOSD 患者的冠层 FGF 信号调节因子 3 (CNPY3) 的一个新变体 C52Y，并证明该变体与 GP96 和 TLR 的相互作用比与野生型 CNPY3 更强。我们发现 C52Y 对 TLR4 表面表达具有显着的负面影响。重要的是，在 LPS 刺激后，感染 C52Y 病毒的 RAW264.7 细胞中 TLR4 表面表达水平降低。我们进一步证明，在 LPS 刺激下，CNPY3 C52Y/+ 转基因小鼠的骨髓源性巨噬细胞 ( ^BMDM )比野生型小鼠的骨髓源性巨噬细胞 (BMDM) 分泌更少的肿瘤坏死因子 (TNF) 和白细胞介素 (IL)-6。这些数据表明 TLR 运输受损可能会导致神经免疫性疾病的发生。