Involvement of IL-1β-Mediated Necroptosis in Neurodevelopment Impairment after Neonatal Sepsis in Rats

Abstract

The mechanism of long-term cognitive impairment after neonatal sepsis remains poorly understood, although long-lasting neuroinflammation has been considered the primary contributor. Necroptosis is actively involved in the inflammatory process, and in this study, we aimed to determine whether neonatal sepsis-induced long-term cognitive impairment was associated with activation of necroptosis. Rat pups on postnatal day 3 (P3) received intraperitoneal injections of lipopolysaccharide (LPS, 1 mg/kg) to induce neonatal sepsis. Intracerebroventricular injection of IL-1β-siRNA and necrostatin-1 (NEC1) were performed to block the production of IL-1β and activation of necroptosis in the brain, respectively. The Morris water maze task and fear conditioning test were performed on P28–P32 and P34–P35, respectively. Enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (RT-PCR), and Western blotting were used to examine the expression levels of proinflammatory cytokines and necroptosis-associated proteins, such as receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Sustained elevation of IL-1β level was observed in the brain after initial neonatal sepsis, which would last for at least 32 days. Sustained necroptosis activation was also observed in the brain. Knockdown of IL-1β expression in the brain alleviated necroptosis and improved long-term cognitive function. Direct inhibition of necroptosis also improved neurodevelopment and cognitive performance. This research indicated that sustained activation of necroptosis via IL-1β contributed to long-term cognitive dysfunction after neonatal sepsis.

Humoral Cytokine Levels in Patients with Herpes Zoster: A Meta-Analysis

“… 67 Additionally, an in-vivo study suggested that IL-1β is involved in neurodevelopment. 68 In conclusion, the onset and progression of PHN may be closely associated with IL-1β, as evidenced by this meta-analysis.…”

IL-1β, the first piece to the puzzle of sepsis-related cognitive impairment?

“…Numerous cell death processes, including necrosis/necroptosis, pyroptosis, and ferroptosis, are connected to the release of DAMPs ( Murao et al, 2021 ). All these different types of cell death have been reported in the pathological development of sepsis and cognitive dysfunction associated with sepsis ( Fu et al, 2019 ; Zhou et al, 2019 ; Chu et al, 2022 ; Liao et al, 2022 ; Wang J. et al, 2022 ; Liao et al, 2023 ). Our recent research showed that necrostatin-1 and xenon were protective against sepsis-induced brain injury by preventing necroptosis.…”

“…Our recent research showed that necrostatin-1 and xenon were protective against sepsis-induced brain injury by preventing necroptosis. Necroptosis was activated via receptor interacting protein 1/3 (RIP1/3), which contributed to impaired neurodevelopment in neonatal sepsis survivors (Liao et al, 2022(Liao et al, , 2023. The NLRP3/caspase-1 pathway-induced pyroptosis has also been linked to cognitive impairment following sepsis.…”

“…Among these pro-inflammatory cytokines, IL-1β is particularly important within the CNS after sepsis ( Wang et al, 2012 ; Pozzi et al, 2018 ). Previous studies have shown that IL-1β, but not TNF-α or IL-6, is the exclusive cytokine within the CNS that has been verified to remain elevated for up to 70 days in rats survived neonatal sepsis but subsequently developed cognitive impairment ( Lan et al, 2015 ; Liao et al, 2023 ). Furthermore, neurodevelopment of neonatal septic rats could be improved by directly antagonizing IL-1β ( Zhang et al, 2022 ).…”