WIF-1通过CRYAB/STAT4-SHH轴对狼疮诱发的神经心理缺陷做出贡献

IF 4.9 2区医学 Q1 Medicine

Arthritis Research & Therapy Pub Date : 2024-10-23 DOI:10.1186/s13075-024-03420-8

Liping Tan, Yu Fan, Xinyi Xu, Tianshu Zhang, Xiangyu Cao, Chenghao Zhang, Jun Liang, Yayi Hou, Huan Dou

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引用次数: 0

摘要

神经精神系统性红斑狼疮（NPSLE）通常表现为认知能力下降，活化的小胶质细胞和血脑屏障（BBB）破坏与这些神经系统并发症有关。在 NPSLE 患者的脑脊液（CSF）中检测到了一种分泌蛋白 Wnt 抑制因子-1（WIF-1）。然而，人们对WIF-1在狼疮认知障碍中的作用仍知之甚少。研究人员利用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，通过脑室内注射给药重组WIF-1蛋白（rWIF-1）和编码sh-WIF-1的腺相关病毒（AAV）。实验采用了行为测试、组织病理学检查、流式细胞术和分子生物学技术来研究其潜在机制。rWIF-1的显微注射加剧了认知障碍和情绪异常，增加了BBB渗漏和神经元变性，并导致海马中小胶质细胞的异常激活和突触修剪。相反，注射了AAV-shWIF-1的狼疮小鼠则表现出明显的病情缓解。在体外，rWIF-1诱导小胶质细胞过度活化，CD86+促炎亚群增加，吞噬活性上调，突触吞噬过度，导致BBB通透性增加。此外，WIF-1 还通过 CRYAB/STAT4 通路发挥其生物效应，转录减少 SHH 的产生。我们还发现，对称二甲基精氨酸（SDMA）可缓解 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轴引发异常的小胶质细胞活化和BBB破坏，从而加剧了狼疮诱导的小鼠认知功能障碍，这凸显了SDMA治疗NPSLE的潜在疗效。

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WIF-1 contributes to lupus-induced neuropsychological deficits via the CRYAB/STAT4-SHH axis

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.

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来源期刊

Arthritis Research & Therapy RHEUMATOLOGY-

CiteScore

8.60

自引率

2.00%

发文量

261

审稿时长

14 weeks

期刊介绍： Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.