Abstract
The Wnt/β-catenin pathway has been involved in regulating inflammation in various infectious and inflammatory diseases. Sepsis is a life-threatening condition caused by dysregulated inflammatory response to infection with no effective therapy available. Recently elevated Wnt/β-catenin signaling has been detected in sepsis. However, its contribution to sepsis-associated inflammatory response remains to be explored. In this study, we show that inhibition of Wnt/β-catenin signaling reduces inflammation and mitigates sepsis-induced organ injury. Using in vitro LPS-stimulated RAW264.7 macrophages, we demonstrate that a small-molecule inhibitor of β-catenin responsive transcription, iCRT3, significantly reduces the LPS-induced Wnt/β-catenin activity and also inhibits TNF-α production and IκB degradation in a dose-dependent manner. Intraperitoneal administration of iCRT3 to C57BL/6 mice, subjected to cecal ligation and puncture-induced sepsis, decreases the plasma levels of proinflammatory cytokines and organ injury markers in a dose-dependent manner. The histological integrity of the lungs is improved with iCRT3 treatment, along with reduced lung collagen deposition and apoptosis. In addition, iCRT3 treatment also decreases the expression of the cytokines, neutrophil chemoattractants, as well as the MPO activity in the lungs of septic mice. Based on these findings we conclude that targeting the Wnt/β-Catenin pathway may provide a potential therapeutic approach for treatment of sepsis.
Highlights
Sepsis is defined as a clinical syndrome due to dysregulated systemic immune response to infection that causes multiple organ failure and could be life-threatening[1]
We examined the effect of treatment with iCRT3 on inflammation and organ injury in mice with sepsis induced by cecal ligation and puncture (CLP), a physiologically relevant model
We further quantified the severity of Cultured RAW 264.7 cells were pre-treated with iCRT3 at the indicated concentration for 50 min and stimulated with LPS (1 ng/ml). (A) Before treatment, RAW264.7 macrophage cells were co-transfected with β-catenin/T-cell factor (TCF) response reporter TOP-TK-Luc or its control FOP-TK-Luc and an internal control pRL-TK
Summary
Sepsis is defined as a clinical syndrome due to dysregulated systemic immune response to infection that causes multiple organ failure and could be life-threatening[1]. A recent study showed that Wnt inhibitors suppress LPS-induced inflammatory responses, hinting that a therapeutic strategy designed to attenuate Wnt/β-catenin signaling has the potential to prevent sepsis-induced inflammation[24]. We examined the effect of treatment with iCRT3 on inflammation and organ injury in mice with sepsis induced by cecal ligation and puncture (CLP), a physiologically relevant model. This approach further elaborated the role of β-catenin-TCF mediated Wnt signaling in regulating sepsis-induced inflammation and organ injury and evaluated the potential of using Wnt/β-catenin signaling-inhibitors as a therapeutic strategy for treating sepsis-induced lung damage
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