Abstract
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals—with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.
Highlights
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals— with or without trauma exposure
The goal of our study was to use the radiotracer [11C]PBR28 and positron emission tomography (PET) brain imaging to measure a marker of the neuroimmune system in PTSD. [11C]PBR28 targets the 18-kDa translocator protein (TSPO), which is a mitochondrial outer membrane protein expressed in microglia, and a molecule that has been extensively studied as a biomarker of microglia in humans with PET brain imaging27. [11C]PBR28 is a second-generation PET radioligand with high specific binding to TSPO28, favorable kinetics, and good reproducibility in quantifying TSPO availability[29]
Observations of M1-predominant activation did not result in any increase in TSPO in in vitro human microglia cell culture[46], while TSPO overexpression was associated with M2-predominant activation and reduced proinflammatory cytokine production in rodent microglial cells[47]
Summary
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD. [11C]PBR28 Positron Emission Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals— with or without trauma exposure. An independent postmortem study found no differential gene expression in 22 PTSD vs 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology. Peripheral immune modulators, including cytokines, are thought to affect PTSD pathophysiology by traversing the blood–brain barrier and acting on microglia, the resident immune cells of the central nervous system These actions have been thought to trigger immunologic activation of microglia, which subsequently release pro- and anti-inflammatory cytokines that modify the brain response to stress, as observed in rodent models of stress and PTSD19–21. In an independent dataset of postmortem brain tissue from individuals with and without PTSD, we examined transcript expression of TSPO and other microglia-associated genes that may be differentially expressed in relation to PTSD, to better understand what is likely a complex interaction of TSPO with other molecules to produce PTSDrelated neuroimmune system alterations
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