Lipopolysaccharide induced long-term tolerance in microglia: Transcriptome profiling
Keita Saeki1, Richard Pan1, Keiko Ozato1 1Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD, 20892, USA
Systemic infection of gram-negative bacteria or peripheral injection of bacterial lipopolysaccharide (LPS) causes sepsis/LPS associated encephalopathy which changes brain metabolism and circulation and regulates neuroinflammation. LPS associated encephalopathy is thus thought to critically control neuronal health and alter existing brain disorders. Although underlying mechanisms are poorly understood, it has been shown that systemic LPS injection c activates microglia, inducing inflammatory genes. In periphery, exposure to LPS causes a temporary state of unresponsiveness, termed “LPS Tolerance” where LPS inducible inflammatory genes are not induced for up to 7-10 days, after which LPS response returns. This tolerance is attributed to macrophages. However, LPS tolerance in microglia has not been well studied so far. We injected C57BL/6 mice with LPS via i.p, followed by 2nd LPS rechallenge after varying intervals and performed RNA-seq for isolated microglia. More than 1.000 genes were induced in microglia by LPS, some were shared with those induced in peripheral macrophages. The patterns and kinetics of LPS induced transcription appeared to differ between peripheral macrophages and microglia. We found that LPS tolerance lasts more than 12 weeks in microglia, much longer than that in in peripheral macrophages reported. Both proinflammatory cytokine/chemokine genes and IFN stimulated genes (ISGs) induced via a feedback mechanism were in prolonged tolerance. These results raise the possibility that prolonged LPS tolerance causes lasting epigenetic changes in the microglia transcriptome landscape, and may be as a mechanism by which LPS exposure affects brain's health and disease state.