Mitigation of sepsis-induced inflammatory responses and organ injury through targeting Wnt/β-catenin signaling

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.

The deacetylase sirtuin 6 protects against kidney fibrosis by epigenetically blocking β-catenin target gene expression

“…Since Wnt/b-catenin signaling is a major pathway involving in renal fibrosis, and Sirt6 has been reported to control Wnt signaling in hematopoietic stem cell homeostasis, 28,32 b-catenin-responsive transcription inhibitor, iCRT3. 33 We first confirmed the effect of iCRT3 on b-catenin activity by glucose induction. 35,36 It is unclear whether Sirt6 might act as a deacetylase for b-catenin in the context of fibrogenesis.…”

Long noncoding RNA HOXA‐AS2 mediates microRNA‐106b‐5p to repress sepsis‐engendered acute kidney injury

“…[ 36,37 ] A report showed that suppression of Wnt/β‐catenin could abate inflammation, meanwhile assuage sepsis‐engendered organ damage. [ 38 ] On the other hand, Chen et al [ 32 ] and Huang et al [ 39 ] have revealed that lncRNA NEAT1 and PVT1 affected LPS‐triggered septic AKI through regulation of the NF‐κB pathway. In our research, we also want to confirm whether Wnt/β‐catenin and NF‐κB signaling influences the protection of HOXA‐AS2 in sepsis‐triggered AKI.…”

Lysyl hydroxylase 3 increases collagen deposition and promotes pulmonary fibrosis by activating TGFβ1/Smad3 and Wnt/β-catenin pathways

“…Moreover, disruption of the pyridine cross-linking formation affects collagen synthesis of ECM and decreases fibrotic lesions. It was previously discovered that iCRT3 blocks signaling transduction of Wnt/β-catenin and TGFβ1/Smad3 [14,15], thus inhibiting downstream lysyl hydroxylase 3 gene and protein expression. It was postulated that iCRT3 might possess anti-fibrotic properties by reducing the total number of lysine pyridinoline cross-links and hydroxyallysine pyridinoline cross-linking formation.…”

“…iCRT3 is a small molecule inhibitor of the Wnt/β-catenin signaling pathway. Its inhibition is achieved through blocking β-catenin nuclear transfer, inhibiting Wnt/β-catenin signaling transduction [14,15]. TGF-β acts as a key factor whose activation has been implicated in both pulmonary fibrosis (PF) and airway remodeling in this process [16].…”