Sepsis-associated encephalopathy (SAE) is a frequent and devastating central nervous system complication of sepsis and portends a poor prognosis. Accumulating data implicate C-type lectin domain family 7 member A (Clec7a) in neuroinflammation and cognitive impairment, however, its specific role in SAE-linked cognitive impairment remains to be defined. Adult male mice received a single intraperitoneal injection of lipopolysaccharide (LPS, 5 mg·kg⁻¹ i.p.) to induce SAE. Four hours later, animals were treated with the Clec7a antagonist laminarin (250 mg·kg⁻¹ i.p.) once daily for three days. Cognitive performance was assessed on days 6-9 post-LPS using the open field, novel object recognition, and Y-maze tests. Hippocampal Clec7a expression was evaluated by Western blotting; microglial number and morphology, myelin integrity, and neuronal activity were assessed by immunofluorescence, Whole-Cell Recordings and transmission electron microscopy. SAE was characterized by marked upregulation of Clec7a and robust microglial activation in the CA1 region of the hippocampus. The LPS challenge increased Clec7a and CD68 expression, triggered excessive microglial phagocytosis of myelin, provoked axonal degeneration and nodal elongation, and reduced neuronal activity - as electrophysiologically demonstrated by hyperpolarized resting membrane potential(RMP), a trend toward an elevated rheobase current, and a decrease in the number of action potentials - along with decreased c-Fos⁺ cell numbers, ultimately leading to cognitive impairment. Laminarin treatment substantially attenuated microglial activation, preserved myelin architecture, restored neuronal activity (evidenced by normalized electrophysiological parameters), increased c-Fos⁺ cell numbers, and rescued cognitive impairment. Clec7a drives microglial activation, leading to aberrant myelin phagocytosis, neuronal hypoactivity, and cognitive impairment in SAE. Pharmacological inhibition of Clec7a reverses these alterations, highlighting Clec7a as a potential therapeutic target for SAE.
Jian et al. (Fri,) studied this question.