Human in vivo neuroimaging to detect reprogramming of the cerebral immune response following repeated systemic inflammation

•The innate immune memory within the CNS may affect neuropsychiatric conditions.•An initial LPS challenge induced robust glial activation diffuse through the brain.•After a subsequent LPS challenge, we observed reduced cerebral TSPO binding.•This suggests reprogramming of the brain immune response towards immunotolerance.•Cerebral immunotolerance may serve as neuroprotective mechanism and treatment target. Despite increasing evidence that immune training within the brain may affect the clinical course of neuropsychiatric diseases, data on cerebral immune tolerance are scarce. This study in healthy volunteers examined the trajectory of the immune response systemically and within the brain following repeated lipopolysaccharide (LPS) challenges. Five young males underwent experimental human endotoxemia (intravenous administration of 2 ng/kg LPS) twice with a 7-day interval. The systemic immune response was assessed by measuring plasma cytokine levels. Four positron emission tomography (PET) examinations, using the translocator protein (TSPO) ligand 18F-DPA-714, were performed in each participant, to assess brain immune cell activation prior to and 5 hours after both LPS challenges. The first LPS challenge caused a profound systemic inflammatory response and resulted in a 53% [95%CI 36–71%] increase in global cerebral 18F-DPA-714 binding (p