The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China.
The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
J Neuroimmunol. 2021 Aug 15;357:577620. doi: 10.1016/j.jneuroim.2021.577620. Epub 2021 May 27.
Neuropsychiatric systemic lupus erythematosus (NPSLE) is the most serious and complicated clinical manifestation of lupus erythematosus. Cognitive dysfunction is the most common symptom of NPSLE. A variety of potential mechanisms or mediators related to the pathogenesis of NPSLE cognitive dysfunction have been proposed. However, the involvement of microglia CD40 has not been reported yet. This study aimed to investigate whether hippocampal microglia CD40 of MRL/MpJ-Fas (MRL/lpr) mice was involved in NPSLE cognitive dysfunction. This study found, using quantitative polymerase chain reaction, western blotting and immunohistochemistry, that hippocampal CD40 was aberrantly overexpressed in the MRL/lpr lupus mice. It also determined using flow cytometry and immunofluorescence that the aberrantly overexpressed CD40 was mainly derived from hippocampal microglia. The adeno-associated virus was used to inhibit microglia CD40 expression, and the brain damage and cognitive dysfunction of MRL/lpr mice improved. Also, imiquimod (IMQ)-induced lupus mice had the same NPSLE cognitive dysfunction, brain damage, and overexpressed hippocampal microglia CD40 as MRL/lpr mice. Therefore, IMQ-induced lupus mouse was proposed as one of the mouse models for studying NPSLE cognitive dysfunction for the first time in this study. The findings indicated that hippocampal microglia CD40 was involved in the development of NPSLE cognitive dysfunction, thus providing a novel research direction for the study of the pathogenesis of NPSLE.
神经精神性狼疮（NPSLE）是红斑狼疮最严重和最复杂的临床表现。认知功能障碍是 NPSLE 的最常见症状。已经提出了多种与 NPSLE 认知功能障碍发病机制相关的潜在机制或介质。然而，尚未报道微胶质细胞 CD40 的参与。本研究旨在探讨 MRL/MpJ-Fas（MRL/lpr）狼疮小鼠海马微胶质细胞 CD40 是否参与 NPSLE 认知功能障碍。本研究通过定量聚合酶链反应、蛋白质印迹和免疫组织化学发现，MRL/lpr 狼疮小鼠海马 CD40 异常过表达。还通过流式细胞术和免疫荧光法确定，异常过表达的 CD40 主要来源于海马小胶质细胞。使用腺相关病毒抑制小胶质细胞 CD40 表达，可改善 MRL/lpr 小鼠的脑损伤和认知功能障碍。此外，咪喹莫特（IMQ）诱导的狼疮小鼠与 MRL/lpr 小鼠具有相同的 NPSLE 认知功能障碍、脑损伤和过表达的海马微胶质细胞 CD40。因此，本研究首次提出 IMQ 诱导的狼疮小鼠作为研究 NPSLE 认知功能障碍的小鼠模型之一。研究结果表明，海马微胶质细胞 CD40 参与了 NPSLE 认知功能障碍的发展，为研究 NPSLE 发病机制提供了新的研究方向。
