Using a mouse model of sepsis and BV2 microglia cultures to assess the effects of CD137 stimulation and CD137L neutralization, in this study we highlight a critical role for the CD137/CD137L axis in promoting sepsis-induced, microglia-mediated neuroinflammation and determining anxiety-cognitive and behavioral deficits characteristic of SAE. This evidence concerns the gene TNFRSF9 and Anxiety.