NLRP3 inflammasome of microglia promotes A1 astrocyte transformation, neo-neuron decline and cognition impairment in endotoxemia

Abstract

Infection, predominantly induced by gram-negative bacteria, is a critical health problem and a leading cause of death worldwide. Advance of techniques, such as antibiotics and life-supporting modality, allows a decreasing death rate of patients with infection in recent decades. Nevertheless, infection-associated complications, in particular cognitive dysfunction, largely influence the mortality of patients and the life quality of survivors. However, the effective medicine is still scant due to the poor interpretion of underlying mechanisms. Herein, we determined multiple cytokines of cerebrospinal fluid in mice challenged with various doses of lipopolysaccharides (LPS)-a pathogenic component of gram-negative bacteria, and found that IL-1β, the downstream of NLRP3 inflammasome, was boosted to a peak extent after a challenge of LPS in high dose. Genetically knockout of Nlrp3 or the downstreams, such as Asc and Gsdmd, dramatically restored LPS-induced cognitive impairment, which was attributed to inhibiting microglia-induced A1 astrocytes and so-caused neo-neuron decline. Taken together, NLRP3 inflammasome of microglia promotes transformation of A1 astrocytes and consequently exacerbates neo-neuron decline, resulting in cognitive impairment after a challenge of LPS. Our study thus discovers a novel understanding in the pathogenesis of LPS-induced cognitive dysfunction, and indicates that NLRP3 inflammasome would be a promising target in the treatment of the syndrome.