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Endotoxin-induced systemic inflammation activates microglia: [¹¹C]PBR28 positron emission tomography in nonhuman
Jonas Hannestad1, Jean-Dominique Gallezot, Thomas Schafbauer
1Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA. jonas.hannestad@yale.edu
Unlabelled:
Microglia play an essential role in many brain diseases. Microglia are activated by local tissue damage or inflammation, but systemic inflammation can also activate microglia. An important clinical question is whether the effects of systemic inflammation on microglia mediate the deleterious effects of systemic inflammation in diseases such as Alzheimer's dementia, multiple sclerosis, and stroke. Positron Emission Tomography (PET) imaging with ligands that bind to Translocator Protein (TSPO) can be used to detect activated microglia. The aim of this study was to evaluate whether the effect of systemic inflammation on microglia could be measured with PET imaging in nonhuman primates, using the TSPO ligand [(11)C]PBR28.
Methods:
Six female baboons (Papio anubis) were scanned before and at 1h and/or 4h and/or 22 h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1mg/kg), which induces systemic inflammation. Regional time-activity data from regions of interest (ROIs) were fitted to the two-tissue compartmental model, using the metabolite-corrected arterial plasma curve as input function. Total volume of distribution (V(T)) of [(11)C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in V(T) from baseline. Serum levels of tumor necrosis factor alpha (TNFα), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) were used to assess correlations between systemic inflammation and microglial activation. In one baboon, immunohistochemistry was used to identify cells expressing TSPO.
Results:
LPS administration increased [(11)C]PBR28 binding (F(3,6)=5.1, p=.043) with a 29 ± 16% increase at 1h (n=4) and a 62 ± 34% increase at 4h (n=3) post-LPS. There was a positive correlation between serum IL-1β and IL-6 levels and the increase in [(11)C]PBR28 binding. TSPO immunoreactivity occurred almost exclusively in microglia and rarely in astrocytes.
Conclusion:
In the nonhuman-primate brain, LPS-induced systemic inflammation produces a robust increase in the level of TSPO that is readily detected with [(11)C]PBR28 PET. The effect of LPS on [(11)C]PBR28 binding is likely mediated by inflammatory cytokines. Activation of microglia may be a mechanism through which systemic inflammatory processes influence the course of diseases such as Alzheimer's, multiple sclerosis, and possibly depression.
Insights
Systemic inflammation activates microglia, a key factor in brain diseases. Positron Emission Tomography (PET) with [(11)C]PBR28 successfully detected this microglial activation in nonhuman primates, offering a new imaging tool.
Area of Science:
- Neuroscience
- Immunology
- Medical Imaging
Background:
- Microglia are crucial in brain diseases and can be activated by systemic inflammation.
- Systemic inflammation's role in neurodegenerative diseases like Alzheimer's and stroke is a significant clinical question.
- Positron Emission Tomography (PET) with Translocator Protein (TSPO) ligands can visualize activated microglia.
Purpose of the Study:
- To determine if PET imaging using the TSPO ligand [(11)C]PBR28 can detect systemic inflammation-induced microglial activation in nonhuman primates.
- To investigate the correlation between systemic inflammatory markers and microglial activation.
Main Methods:
- Six female baboons received intravenous E. coli lipopolysaccharide (LPS) to induce systemic inflammation.
- PET scans with [(11)C]PBR28 were performed before and after LPS administration.
- Serum cytokine levels (TNFα, IL-1β, IL-6, IL-8) were measured, and immunohistochemistry was used to identify TSPO-expressing cells.
Main Results:
- LPS administration significantly increased [(11)C]PBR28 binding in the brain, indicating heightened microglial activation.
- A 29% increase in binding was observed at 1 hour and a 62% increase at 4 hours post-LPS.
- Increased binding positively correlated with serum levels of IL-1β and IL-6, and TSPO was primarily found on microglia.
Conclusions:
- Systemic inflammation robustly increases TSPO levels in the nonhuman primate brain, detectable by [(11)C]PBR28 PET.
- Inflammatory cytokines likely mediate the observed increase in TSPO binding.
- Microglial activation by systemic inflammation may be a key mechanism influencing the progression of neurological diseases.
