IL-17A deletion reduces sevoflurane-induced neurocognitive impairment in neonatal mice by inhibiting NF-κB signaling pathway

Abstract

We investigated the role of IL-17A in sevoflurane-inducedneurocognitive impairment in neonatal mice. Seventy-two wild-type (WT) and 42 IL-17A knockout (KO) neonatal mice were randomly divided into WT ( n = 36), IL-17A −/− ( n = 6), sevoflurane (Sev, n = 36), and IL-17A −/− + sevoflurane (IL-17A −/− + Sev, n = 36) groups. The latter two groups were given 3% sevoflurane for 2 h per day on postnatal days (P) 6–8. Behavioral experiments were performed on P30–36. At P37, RNA sequencing and qRT-PCR of the hippocampus was performed, neurons were detected by Nissl staining, and neuropathological changes were evaluated by HE staining. NF-κB pathway-related proteins were evaluated by western blot and immunofluorescence analyses, IL-1β and IL-6 levels were assessed by ELISA. RNA sequencing identified 131 differentially expressed genes, highlighting several enriched biological processes (chemokine activity, immune response, extracellular region, extracellular space, inflammatory response) and signaling pathways (IL-17 signaling pathway, chemokine signaling pathway, cytokine–cytokine receptor interaction, ECM–receptor interaction and influenza A). Repeated sevoflurane exposures induced long-term cognitive impairment in WT mice. The cognitive impairment was comparatively less severe in IL-17A KO mice. In addition, the increased levels of NF-κB p65, iNOS, COX-2, IL-17A, IL-6 and IL-1β, reduced neuronal numbers and neuropathological changes were ameliorated in neonatal mice in the IL-17A −/− + Sev group compared with neonatal mice in Sev group. IL-17A deletion protects against long-term cognitive impairment induced by repeated sevoflurane exposure in neonatal mice. The underlying mechanism may relate to inhibiting NF-κB signaling pathway as well as the reducing neuroinflammation.

Taxifolin ameliorates IL-17A-enhanced hippocampal inflammation and oxidative stress in arsenic-exposed HT-22 cells

“…Accretion of ROS as a consequence of As-promoted oxidative stress can interfere with inflammation pathways through protein kinase C activation as evidenced by elevated levels of pro-inflammatory cytokines [15]. IL-17A is a pivotal inflammatory mediator exacerbating chronic tissue inflammation, triggering multiple signaling molecules like TNF-α, IL-1β, and IL-6 [13,14]. To explore the specific role of taxifolin on hippocampal inflammation in NaAsO2-treated cells, we evaluated IL-17A and its related inflammatory cytokines including TNF-α, IL-1β and IL-6.…”

“…IL-17A promotes secretion of pro-inflammatory cytokines, like IL-1β and IL-6, which aggravates the inflammatory response including cerebral ischemia-reperfusion injury and Alzheimer's disease [11,12]. According to recent research, IL-17A leads to impaired neurocognitive functions by activating downstream inflammatory pathways which may amplify inflammation via the secretion of IL-1β and IL-6 cytokines [13]. In addition, Yang et al reported that anti-IL-17A treatment alleviates neuroinflammation by reducing TNF-α, IL-1β, and IL-6 proinflammatory cytokines and oxidative damage via strengthening antioxidant defense mechanism in the hippocampus [14].…”