The Absence of Gasdermin D Reduces Nuclear Autophagy in a Cecal Ligation and Puncture-Induced Sepsis-Associated Encephalopathy Mouse Model

Abstract

Sepsis-associated encephalopathy (SAE) is a common complication of sepsis, which is a life-threatening condition resulting from a dysregulated host response to infection. Pyroptosis, a pro-inflammatory mode of lytic cell death mediated by GSDMD (Gasdermin D), is involved in the pathogenesis of SAE. While autophagy has been extensively studied in SAE, the role of nuclear autophagy is not yet well understood. In this study, we aimed to investigate the involvement of pyroptosis and neural nuclear autophagy in the pathogenesis of SAE. We analyzed a CLP (cecal ligation and puncture)-induced SAE model in wild-type and GSDMD−/− mice to gain insights into the underlying mechanisms. Here, we show that in sepsis, neural nuclear autophagy is extremely activated, and nuclear LaminB decreases and is accompanied by an increase in the ratio of LC3BII/I. These effects can be reversed in GSDMD−/− mice. The behavioral outcomes of septic wild-type mice are impaired by the evidence from the novel object recognition test (NORT) and open field test (OFT), but are improved in septic GSDMD−/− mice. In conclusion, our study demonstrates the activation of neural nuclear autophagy in SAE. The absence of GSDMD inhibits nuclear autophagy and improves the behavioral outcomes of SAE.

GSDMD/Drp1 signaling pathway mediates hippocampal synaptic damage and neural oscillation abnormalities in a mouse model of sepsis-associated encephalopathy

“…The present study confirms that GSDMD is indeed involved in the release of proinflammatory cytokines IL-1β and IL-18 in the context of SAE, consistent with previous research [10]. Sepsis-induced nuclear autophagy might be linked to mitochondrial damage through GSDMD, providing a potential mechanistic insight into the pathology of SAE [12]. The study further explores the therapeutic potential of targeting GSDMD-mediated mitochondrial damage in the treatment of SAE.…”

“…Additionally, pharmacological inhibition of the NLRP3-caspase-1 inflammasome has demonstrated a reduction in the expression of both GSDMD and its cleavage form, GSDMD-N, effectively mitigating pyroptosis in the mouse brain following sepsis [10,11]. Furthermore, GSDMD knockout mice exhibited improved behavioral outcomes after sepsis [12].…”