Ketamine inhibits TNF-α-induced cecal damage by enhancing RIP1 ubiquitination to attenuate lethal SIRS

Abstract

Systemic inflammatory response syndrome (SIRS) is a sepsis-associated inflammatory state and a self-defense mechanism against specific and nonspecific stimuli. Ketamine influences many key processes that are altered during sepsis. However, the underlying mechanisms remain incompletely understood. In this study, TNF-α-treated mice, as well as HT-29 and L929 cell models, were applied to characterize TNF-α-induced systemic and local cecal tissue inflammatory responses. Behavioral, biochemical, histological, and molecular biological approaches were applied to illustrate the related processes. Mice with TNF-α-induced SIRS showed systemic and local cecal tissue inflammatory responses, as indicated by increased levels of high mobility group box 1 protein (HMGB1), chemokines (C-X-C motif) ligand 10 (CXCL10), interleukin-6 (IL-6), and IL-10, as well as high mortality. Ketamine pretreatment alleviated death rates, symptoms, and the production of inflammatory cytokines induced by TNF-α in mice. Moreover, ketamine also protected the mice from TNF-α-induced cecal damage by suppressing the phosphorylation of receptor-interacting serine/threonine-protein kinase 3 (RIP3) and mixed lineage kinase domain-like protein (MLKL). In addition, our results showed that ketamine efficiently inhibited TNF-α-induced necroptosis in HT-29 and L929 cells. Furthermore, we explored the mechanism using different L929 cell lines. The results displayed that ketamine inhibited TNF-α-induced necroptosis by enhancing RIP1 ubiquitination and reducing the RIP1-RIP3 and RIP3-MLKL interactions, as well as the formation of necrosomes. Thus, our study may provide a new theoretical and experimental basis for treating diseases characterized by SIRS-associated inflammatory factor storms. Moreover, our exploration may provide potential molecular mechanisms and targets for therapeutic intervention and clinical application of ketamine.

WITHDRAWN: Ketamine alleviated blood-brain barrier damage and microglia over-activation induced by SIRS via restricting cecum damage and HMGB1 release

“…Cecum plays a critical role during the SIRS process. Our previous study has detected severe damage and necroptosis that occurred in the cecum of TNF-induced SIRS mice 9 . More speci cally, consolidated evidence has also suggested that cecum damage increased circulating HMGB1 levels and elevated in ammatory cytokines released by over-activated microglia and led to a neurological disorder, thereafter 39,40 .…”

“…Although ketamine inhibits HMGB1 production via multiple mechanism 7 , our previous work had represented the protective effect of ketamine on the neuron, L929 cell, and cecal epithelial cell by inhibiting phosphorylation of MLKL, restricting necroptosis 8,9 . However, a few research focus on the role of ketamine in the neurovascular unit like BBB.…”

Ketamine role in the treatment of Maternal depression: effects on offspring behaviour

“…However, it remains concerning that despite alleviating offspring behaviour, uoxetine still crosses the placenta and acts directly on the foetal brain during vulnerable developmental periods with unpredictable echo effects that may not manifest until adolescence or adulthood (Houwing et al 2019). Ketamine, in contrast, has not been shown to accumulate in foetal tissue or breastmilk, conferring an advantage (Deng et al 2022).…”

The pathogenesis and potential therapeutic targets in sepsis

“…In contrast to caspase‐dependent programmed cell death, necroptosis is an unprogrammed and autonomous form of cell death that can be activated by various virulence factors discharged by the pathogen. However, sepsis‐induced changes in organ perfusion and hypovolemia can also contribute to necrosis 178 . This process, in turn, can bolster the release of extracellular “alarm proteins” such as HMGB1, thereby exacerbating local inflammation.…”