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Resveratrol attenuates TLR-4 mediated inflammation and elicits therapeutic potential in models of sepsis
Binbin Wang1,2, Gregory Lucien Bellot1,3, Kartini Iskandar1
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
Abstract:
Sepsis is a potentially fatal condition triggered by systemic inflammatory response to infection. Due to the heightened immune reactivity and multi-organ pathology, treatment options are limited and several clinical trials have not produced the desired outcome, hence the interest in the discovery of novel therapeutic strategies. The polyphenol resveratrol (RSV) has shown promise against several pathological states, including acute and chronic inflammation. In this study, we evaluated its therapeutic potential in a murine model of sepsis and in patients undergoing transrectal ultrasound biopsy. RSV was able to inhibit lipopolysaccharide (LPS) stimulated inflammatory responses through blocking Phospholipase D (PLD) and its downstream signaling molecules SphK1, ERK1/2 and NF-κB. In addition, RSV treatment resulted in the downregulation of MyD88, an adaptor molecule in the TLR4 signaling pathway, and this effect at least in part, involved RSV-induced autophagy. Notably, RSV protected mice against polymicrobial septic shock induced upon cecal ligation and puncture, and inhibited pro-inflammatory cytokine production by human monocytes from transrectal ultrasound (TRUS) biopsy patients. Together, these findings demonstrate the immune regulatory activity of RSV and highlight its therapeutic potential in the management of sepsis.
Insights
Resveratrol (RSV) effectively reduces inflammation in sepsis by blocking key signaling pathways. This natural compound shows therapeutic potential for managing sepsis and related inflammatory conditions.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Sepsis is a life-threatening systemic inflammatory response to infection with limited treatment options.
- Novel therapeutic strategies are needed due to high mortality and clinical trial failures.
- Resveratrol (RSV), a polyphenol, exhibits anti-inflammatory properties beneficial in various pathological conditions.
Purpose of the Study:
- To investigate the therapeutic potential of resveratrol (RSV) in a murine sepsis model.
- To evaluate RSV's effects on inflammatory responses in human monocytes from patients undergoing transrectal ultrasound (TRUS) biopsy.
- To elucidate the molecular mechanisms underlying RSV's anti-inflammatory actions.
Main Methods:
- RSV's effect on lipopolysaccharide (LPS)-stimulated inflammatory responses was assessed.
- Key signaling molecules including Phospholipase D (PLD), SphK1, ERK1/2, and NF-κB were analyzed.
- The role of MyD88 downregulation and RSV-induced autophagy in the TLR4 pathway was investigated.
- Therapeutic efficacy was tested in a murine model of polymicrobial septic shock (cecal ligation and puncture).
Main Results:
- RSV inhibited LPS-induced inflammatory responses by blocking PLD and its downstream signaling.
- RSV downregulated MyD88, a TLR4 pathway adaptor, partly via induced autophagy.
- RSV treatment protected mice from septic shock and reduced pro-inflammatory cytokine production in human monocytes.
- RSV demonstrated significant immune regulatory activity.
Conclusions:
- Resveratrol exhibits potent anti-inflammatory and immune-regulatory effects relevant to sepsis.
- RSV's mechanism involves blocking key inflammatory signaling pathways and modulating the TLR4 pathway.
- RSV shows promise as a therapeutic agent for sepsis management.
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