Nature 556, 332–338 (2018)

Epigenetically mediated immunological imprinting can manifest as training or tolerance, which enhance inflammation or suppress it, respectively. In Nature, Neher and colleagues show that one intraperitoneal injection of LPS (1×LPS) induces training, while treatment with four injections of LPS (4×LPS) induces tolerance in brain microglia, manifested by the respective increased or decreased induction of the inflammatory cytokines TNF, IL-1β and IL-6 in the brain. In APP2 mice, a model of Alzheimer’s disease, or in mice with induced ischemia, 1×LPS increases neuropathology, while 4×LPS decreases it. Training (1×LPS) induces the amplification of inflammation-related pathways, such as HIF-1α-dependent signaling and a metabolic switch to glycolysis, that are already upregulated in APP2 mice relative to their activity in wild-type mice, while tolerance (4×LPS) downregulates these pathways. The effect of other inflammatory stimuli remains to be tested.