Cognitive impairment, acute or long-term, is a common complication in patients with severe bacterial infection. However, the underlying mechanisms are not fully verified and effective medicine is not available in clinics. Interferon gamma (IFN gamma) is a pivotal cytokine against infection and is believed to be a tune in homeostasis of cognitive function. Here, we collected blood and cerebrospinal fluid (CF) from human subjects and mice, and found that plasma and CF levels of IFN gamma were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFN gamma signaling was boosted in the hippocampus of mice after a challenge of lipopolysaccharide (LPS), which was accompanied with cognitive impairment and decline of neurogenesis. Deficiency of IFN gamma or its receptor (IFN gamma R) dramatically attenuated microglia-induced A1 astrocytes and consequently restored neurogenesis and cognitive function in endotoxemia mice model. Using primary microglia, astrocytes and neurons, we found that IFN gamma remarkably increased LPS-mediated release of TNF alpha and IL-1 alpha in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFN gamma promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFN gamma would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection. (C) 2020 Elsevier Inc. All rights reserved.