Neuropsychiatric systemic lupus erythematosus (NPSLE) often manifests as cognitive deterioration, with activated microglia and blood-brain barrier (BBB) disruption implicated in these neurological complications. Wnt-inhibitory factor-1 (WIF-1), a secreted protein, has been detected in the cerebrospinal fluid (CSF) of NPSLE patients. However, the contribution of WIF-1 in contributing to lupus cognitive impairment remains poorly understood. Using MRL/MpJ-Faslpr (MRL/lpr) lupus-prone mice and TLR7 agonist imiquimod (IMQ)-induced lupus mice, recombinant WIF-1 protein (rWIF-1) and adeno-associated virus (AAV) encoding sh-WIF-1 were administered via intracerebroventricular injection. Behavioral tests, histopathological examinations, flow cytometry, and molecular biology techniques were employed to investigate the underlying mechanisms. Microinjection of rWIF-1 exacerbated cognitive deficits and mood abnormalities, increased BBB leakage and neuronal degeneration, and caused aberrant activation of microglia and synaptic pruning in the hippocampus. Conversely, lupus mice injected with AAV-shWIF-1 exhibited significant remission. In vitro, rWIF-1 induced overactivation of microglia with an increased CD86+ pro-inflammatory subpopulation, upregulated phagocytic activity, and excessive synaptic engulfment, contributing to increased BBB permeability. Furthermore, WIF-1 exerted its biological effects through the CRYAB/STAT4 pathway, transcriptionally decreasing SHH production. We also identified that symmetric dimethylarginine (SDMA) could alleviate rWIF-1-induced microglial activation and BBB damage, thereby restoring SHH levels. In conclusion, WIF-1 exacerbates lupus-induced cognitive dysfunction in mice by triggering aberrant microglial activation and BBB disruption through the CRYAB/STAT4-SHH axis, highlighting the potential therapeutic effects of SDMA for the treatment of NPSLE.

中文翻译：

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WIF-1 通过 CRYAB/STAT4-SHH 轴促进狼疮诱导的神经心理缺陷


神经精神系统性红斑狼疮 （NPSLE） 通常表现为认知能力下降，这些神经系统并发症与活化的小胶质细胞和血脑屏障 （BBB） 破坏有关。Wnt 抑制因子-1 （WIF-1） 是一种分泌蛋白，已在 NPSLE 患者的脑脊液 （CSF） 中检测到。然而，WIF-1 在导致狼疮认知障碍中的作用仍然知之甚少。使用 MRL/MpJ-Faslpr （MRL/lpr） 狼疮易感小鼠和 TLR7 激动剂咪喹莫特 （IMQ） 诱导的狼疮小鼠，通过脑室内注射给予编码 sh-WIF-1 的重组 WIF-1 蛋白 （rWIF-1） 和腺相关病毒 （AAV）。采用行为测试、组织病理学检查、流式细胞术和分子生物学技术来研究潜在机制。显微注射 rWIF-1 加剧了认知缺陷和情绪异常，增加了 BBB 泄漏和神经元变性，并导致海马体中小胶质细胞和突触修剪的异常激活。相反，注射 AAV-shWIF-1 的狼疮小鼠表现出显着的缓解。在体外，rWIF-1 诱导小胶质细胞过度激活，CD86 + 促炎亚群增加，吞噬活性上调，突触过度吞噬，导致 BBB 通透性增加。此外，WIF-1 通过 CRYAB/STAT4 通路发挥其生物学效应，转录性地降低 SHH 的产生。我们还发现对称二甲基精氨酸 （SDMA） 可以减轻 rWIF-1 诱导的小胶质细胞活化和 BBB 损伤，从而恢复 SHH 水平。 总之，WIF-1 通过 CRYAB/STAT4-SHH 轴触发异常的小胶质细胞激活和 BBB 破坏，加剧了狼疮诱导的小鼠认知功能障碍，突出了 SDMA 治疗 NPSLE 的潜在治疗效果。