2. Academic Validation
  3. Disturbance of neuron-microglia crosstalk mediated by GRP78 in Neuropsychiatric systemic lupus erythematosus mice

Disturbance of neuron-microglia crosstalk mediated by GRP78 in Neuropsychiatric systemic lupus erythematosus mice

  • J Neuroinflammation. 2023 Jun 26;20(1):150. doi: 10.1186/s12974-023-02832-8.
Jingyi Xu # 1,  Chunshu Yang # 2,  Siyuan Zeng 1,  Xuejiao Wang 3,  Pingting Yang 4,  Ling Qin 5
Affiliations

Affiliations

  • 1 Department of Rheumatology and Immunology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
  • 2 Department of 1st Cancer Institute, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.
  • 3 Department of Physiology, School of Life Science, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China.
  • 4 Department of Rheumatology and Immunology, The First Hospital of China Medical University, Shenyang, 110001, People's Republic of China. yangpingtingting@163.com.
  • 5 Department of Physiology, School of Life Science, China Medical University, Shenyang, Liaoning Province, 110122, People's Republic of China. lqin@cmu.edu.cn.
  • # Contributed equally.
PMID: 37365565 DOI: 10.1186/s12974-023-02832-8
Abstract

Objectives: Neuropsychiatric systemic lupus erythematosus (NPSLE) is a serious phenotype of systemic lupus erythematosus (SLE). The disturbance of neuron-microglia crosstalk is recently revealed in many neuropsychiatric diseases but was not well studied in NPSLE. We found glucose regulatory protein 78 (GRP78), a marker of endoplasmic reticulum stress, was significantly increased in the cerebrospinal fluid (CSF) of our NPSLE cohort. We, therefore, investigated whether GRP78 can act as a mediator between the neuron-microglia crosstalk and is involved in the pathogenic process of NPSLE.

Methods: Serum and CSF parameters were analyzed in 22 NPSLE patients and controls. Anti-DWEYS IgG was injected intravenously into mice to establish a model of NPSLE. Behavioral assessment, histopathological staining, RNA-seq analyses, and biochemical assays were performed to examine the neuro-immunological alterations in the mice. Rapamycin was intraperitoneally administered to define the therapeutic effect.

Results: The level of GRP78 was elevated significantly in the CSF of the patients with NPSLE. An increase in GRP78 expression, accompanied by neuroinflammation and cognitive impairment, was also found in the brain tissues of the NPSLE model mice induced by anti-DWEYS IgG deposition on hippocampal neurons. In vitro experiments demonstrated that anti-DWEYS IgG could stimulate neurons to release GRP78, which activated microglia via TLR4/MyD88/NFκB pathway to produce more pro-inflammatory cytokines and promote migration and phagocytosis. Rapamycin ameliorated GRP78-inducing neuroinflammation and cognitive impairment in anti-DWEYS IgG-transferred mice.

Conclusion: GRP78 acts as a pathogenic factor in neuropsychiatric disorders via interfering neuron-microglia crosstalk. Rapamycin may be a promising therapeutic candidate for NPSLE.

Keywords

Glucose regulatory protein 78; Microglia; Neuropsychiatric systemic lupus erythematosus; Rapamycin; Spatial memory.

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