Details

Autor(en) / Beteiligte

• Lu, Yanyan
• Yang, Yanliang
• Peng, Zhouyangfan
• Xie, Lingli
• Zhong, Xiaoli
• Liang, Fang
• Yuan, Chuang
• Lu, Ben

Titel

Silencing IFNγ inhibits A1 astrocytes and attenuates neurogenesis decline and cognitive impairment in endotoxemia

Ist Teil von

• Biochemical and biophysical research communications, 2020-12, Vol.533 (4), p.1519-1526

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (IFNγ) 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 IFNγ were significantly increased in septic patients and endotoxin-challenged mice when compared with healthy controls. IFNγ 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 IFNγ or its receptor (IFNγR) 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 IFNγ remarkably increased LPS-mediated release of TNFα and IL-1α in microglia and consequently induced the transformation of astrocyte to A1 subtype, which ultimately resulted in neuron damage. Thus, IFNγ promotes cognitive impairment in endotoxemia by enhancing microglia-induced A1 astrocytes. Targeting IFNγ would be a novel strategy for preventing or treating cognitive dysfunction in patients with Gram-negative infection. •IFNγ signaling is boosted in septic patients and endotoxemia mice.•Deficiency of IFNγ pathway restores endotoxemia-associated neurogenesis decline and cognitive impairment.•Blocking IFNγ signaling attenuates microglia-mediated A1 astrocytes in endotoxemia.•IFNγ enhances neuron impairment in endotoxemia by promoting microglia activation and consequent A1 astrocytes.