Endotoxin-induced systemic inflammation activates microglia: [11C]PBR28 positron emission tomography in nonhuman primates

Abstract

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 mediates 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 [11C]PBR28. Methods Six female baboons (Papio anubis) were scanned before and at 1 h and/or 4h and/or 22h after intravenous administration of E. coli lipopolysaccharide (LPS; 0.1 mg/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 (VT) of [11C]PBR28 was used as a measure of total ligand binding. The primary outcome was change in VT 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 [11C]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 [11C]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 [11C]PBR28 PET. The effect of LPS on [11C]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.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…Increases in TSPO binding in the brain of nonhuman primates were correlated with increased peripheral blood concentrations of IL-1β, IL-6, and TNF depending on the time point examined after endotoxin administration. Moreover, histological examination confirmed that TSPO binding following endotoxin was primarily increased in microglia as opposed astrocytes that also express TSPO (Hannestad et al, 2012). Interestingly, no correlations between increased peripheral blood cytokine concentrations or increased symptoms of depression and increased TSPO binding in the brain were found after endotoxin in humans, although marked increases in TSPO binding were observed (Sandiego et al, 2015).…”

“…Lowaffinity binders are typically excluded from study analyses, although they represent only ∼ 10% of the population in North America. Proof-of-concept studies have demonstrated increased TSPO binding throughout the brain following administration of endotoxin to both humans and nonhuman primates (Hannestad et al, 2012;Sandiego et al, 2015). Increases in TSPO binding in the brain of nonhuman primates were correlated with increased peripheral blood concentrations of IL-1β, IL-6, and TNF depending on the time point examined after endotoxin administration.…”

The immune response of the human brain to abdominal surgery

“…45,48 In primates, systemic LPS exposure has been shown to cause a significant increase in TSPO binding within 1 to 4 hours, and postmortem immunohistochemistry confirmed a correspondence to microglia/macrophage cells, whereas colocalization of TSPO and astrocyte markers was low. 27 Notably, the initial (<4 hours) increase in global [ 11 C]PBR28 binding was followed by a profound decrease in [ 11 C]PBR28 binding at 22 hours postinjection as measured in a subset of FIGURE 3: FIGURE 3: Ex vivo and plasma cytokines. (A) Ex vivo cytokine production in abdominal surgery patients.…”

“…19,20 TSPO expression is typically elevated in several acute and chronic CNS disorders involving the immune system [21][22][23][24][25] as well as in animal models of acute inflammation 26 or stroke. 19 With regard to periphery-to-brain interactions, lipopolysaccharide (LPS)-induced acute systemic inflammation is followed by a rapid and transient activation of the brain immune system, as demonstrated using the TSPO radioligand [ 11 C]PBR28 in nonhuman primates 27 and humans. 28 Here, we examined the impact of major surgery on the human brain immune system by a longitudinal series of PET examinations of TSPO binding in otherwise healthy patients undergoing abdominal surgery and how changes in glial cell activation relate to systemic inflammatory response and cognitive performance.…”

Imaging robust microglial activation after lipopolysaccharide administration in humans with PET

“…A well-established and robust preclinical model uses the administration of Escherichia coli lipopolysaccharide (LPS; also called endotoxin) to trigger "classic" activation of microglia and has been used in rodents to study neurodegeneration (28)(29)(30)(31). We previously reported a significant increase in [ 11 C]PBR28 binding at 1 (29%) and 4 (62%) hours after LPS administration in nonhuman primates (NHPs) compared with baseline binding levels (32).…”