Abstract
Background: Bipolar disorder (BD) is associated with marked functional impairments along with increased rate of suicide. Although there is ample evidence for the involvement of inflammatory processes and microglia activation in the pathophysiology of BD, the mechanisms that regulate these cells in BD patients, and particularly the role of microglia checkpoints, is still unclear. Methods: Immunohistochemical analyses of hippocampal sections from post-mortem brains of 15 BD patients and 12 control subjects were used to assess microglia density, by staining the microglia-specific receptor P2RY12, and microglia activation, by staining the activation marker MHC II. Given recent findings on the involvement of LAG3, which interacts with MHC II and serves as a negative microglia checkpoint, in depression and electroconvulsive therapy, we assessed the levels of LAG3 expression and their correlations with microglia density and activation. Results: There were no overall differences between BD patients and controls, but BD patients who committed suicide (N = 9) displayed a significant elevation in the overall microglia density and the density of MHC II-labeled microglia (but not other MHC II-labeled cells), compared with no suicide BD patients (N = 6) and controls. Furthermore, the percent of microglia expressing LAG3 was significantly reduced only in suicidal BD patients, with significant negative correlations between microglial LAG3 expression levels and the density of microglia, in general, and activated microglia, in particular. Conclusion: Suicidal BD patients exhibit microglia activation, which is possibly mediated by reduced LAG3 checkpoint expression, suggesting that anti-microglial therapeutics, including LAG3 modulators, may be beneficial for this subgroup of patients.
Original language | American English |
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Pages (from-to) | 185-194 |
Number of pages | 10 |
Journal | Brain, Behavior, and Immunity |
Volume | 110 |
DOIs | |
State | Published - May 2023 |
Bibliographical note
Funding Information:This work was supported by the ISRAEL SCIENCE FOUNDATION grant No. 1379/16 (to R.Y.).
Funding Information:
We thank the Stanley Medical Research Institute for providing the post-mortem brain tissues used in this study. We thank Ms. Zehava Cohen for help in preparation of the figures. This work was supported by the ISRAEL SCIENCE FOUNDATION grant No. 1379/16 (to R.Y.).
Publisher Copyright:
© 2023 Elsevier Inc.
Keywords
- Bipolar disorder
- Hippocampus
- Immune checkpoint
- Lymphocyte Activation Gene 3 (LAG3)
- MHC II
- Microglia
- Mood disorder
- Neuroinflammation
- Post-mortem
- Suicide