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

Autor: Tan L; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China., Fan Y; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China., Xu X; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China., Zhang T; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China., Cao X; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China., Zhang C; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China., Liang J; Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China. 13505193169@139.com., Hou Y; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. yayihou@nju.edu.cn.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. yayihou@nju.edu.cn., Dou H; The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. douhuan@nju.edu.cn.; Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. douhuan@nju.edu.cn.
Jazyk: angličtina
Zdroj: Arthritis research & therapy [Arthritis Res Ther] 2024 Oct 23; Vol. 26 (1), pp. 183. Date of Electronic Publication: 2024 Oct 23.
DOI: 10.1186/s13075-024-03420-8
Abstrakt: Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
Externí odkaz: