Microglia-dependent synapse loss in type I interferon-mediated lupus
Abstract
Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Notably, up to 75% of patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis-collectively this is referred to as central nervous system (CNS) lupus. In some cases, certain autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in most patients, the mechanisms that underlie these symptoms are unknown. CNS lupus typically presents at lupus diagnosis or within the first year, suggesting that early factors contributing to peripheral autoimmunity may promote CNS lupus symptoms. Here we report behavioural phenotypes and synapse loss in lupus-prone mice that are prevented by blocking type I interferon (IFN) signalling. Furthermore, we show that type I IFN stimulates microglia to become reactive and engulf neuronal and synaptic material in lupus-prone mice. These findings and our observation of increased type I IFN signalling in post-mortem hippocampal brain sections from patients with SLE may instruct the evaluation of ongoing clinical trials of anifrolumab, a type I IFN-receptor antagonist. Moreover, identification of IFN-driven microglia-dependent synapse loss, along with microglia transcriptome data, connects CNS lupus with other CNS diseases and provides an explanation for the neurological symptoms observed in some patients with SLE.
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Microglial gene expression changes may contribute to risk for autoimmune disorders of the central nervous system such as multiple sclerosis and lupus.
“Furthermore, work from the past few years demonstrates that microglial gene expression changes during aging and may contribute to risk for AD (3) as well as autoimmune disorders of the central nervous system (CNS) such as multiple sclerosis [MS; reviewed in (4)] and lupus (5), but precisely how these cells contribute to risk for autoimmune disorders or AD remains unclear.”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [5]
Mechanistic dissections of the CNS manifestations of lupus have demonstrated a role for type I interferon signaling and autoantibodies in promoting inappropriate complement- and microglia-mediated engulfment of synapses.
“Strikingly, mechanistic dissections of the CNS manifestations of the autoimmune disorder, lupus, have demonstrated a role for type I interferon signaling and autoantibodies in promoting inappropriate complement- and microglia-mediated engulfment of synapses (5, 106).”
From The Transcriptional Landscape of Microglial Genes in Aging and Neurodegenerative Disease (2019) · cites this paper as [5]
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- Authors
- Bialas, A. R., Presumey, J., Das, A., van der Poel, C. E., Lapchak, P. H., Mesin, L., Victora, G., Tsokos, G. C., Mawrin, C., Herbst, R., & Carroll, M. C.
- Affiliations
- Boston Children's Hospital (US)
- Beth Israel Deaconess Medical Center (US)
- Rockefeller University (US)
- Center for Behavioral Brain Sciences (DE)
- Corresponding author
- Carroll, Michael C.
- ORCID
- Venue
- Nature
- Published
- 2017-06-14
- Volume
- 546
- Issue
- 7659
- Pages
- 539-543
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2625709437
- Cited by
- 197
- References
- 40
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 12 · 2023: 7 · 2022: 11 · 2021: 25 · 2020: 24 · 2019: 37 · 2018: 46 · 2017: 11
- FWCI
- 28.20
- Type
- journal article
- Language
- en
- Status
- Retracted
- Update notices
- retraction (2020-02-05)
- Open access
- closed
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Allergy and Infectious Diseases (R01AI039246, T32AI074549, R01AI042269)
- Topics
- Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Keywords
- systemic lupus erythematosus, neuropsychiatric lupus, type I interferon, microglia, synaptic loss, microglial phagocytosis, microglial activation, cognitive impairment, behavioral phenotypes, anifrolumab, hippocampus, lupus-prone mice
- MeSH terms
- Animals, Antibodies, Monoclonal, Behavior, Animal, Disease Models, Animal, Female, Hippocampus, Humans, Interferon Type I, Male, Phenotype, Synapses, Signal Transduction, Microglia, Lupus Vasculitis, Central Nervous System, Mice, Transcriptome, Antibodies, Monoclonal, Humanized
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