Neuronal MD2 Induces Long-term Mental Impairments in Septic Mice by Facilitating Necroptosis and Apoptosis

Abstract

Sepsis-associated encephalopathy (SAE) is a complication of sepsis that has high morbidity rates. Long-lasting depression is a major mental health disorder in patients with SAE that results in a substantial decrease in quality of life and economic burden. However, the underlying mechanism of SAE is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to depression in sepsis. In a mouse model of cecal ligation and puncture (CLP), we detected mental impairments by the open field test, elevated-plus maze and forced swimming test on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of the septic mice. These mice showed depression-like behaviors at 14 days after CLP, with substantial increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting the function of MD2, the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treatment of mental health issues in sepsis by inhibiting necroptosis and apoptosis.