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CETP Lowers TLR4 Expression Which Attenuates the Inflammatory Response Induced by LPS and Polymicrobial Sepsis
Tatiana Martins Venancio1, Roberta Marcondes Machado1, Angela Castoldi2
1Lipids Laboratory (LIM 10), Faculty of Medical Sciences, The University of São Paulo, São Paulo, SP, Brazil.
Abstract:
Sepsis is a systemic inflammatory response to infection eliciting high mortality rate which is a serious health problem. Despite numerous studies seeking for therapeutic alternatives, the mechanisms involved in this disease remain elusive. In this study we evaluated the influence of cholesteryl ester transfer protein (CETP), a glycoprotein that promotes the transfer of lipids between lipoproteins, on the inflammatory response in mice. Human CETP transgenic mice were compared to control mice (wild type, WT) after polymicrobial sepsis induced by cecal ligation and puncture (CLP), aiming at investigating their survival rate and inflammatory profiles. Macrophages from the peritoneal cavity were stimulated with LPS in the presence or absence of recombinant CETP for phenotypic and functional studies. In comparison to WT mice, CETP mice showed higher survival rate, lower IL-6 plasma concentration, and decreased liver toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) protein. Moreover, macrophages from WT mice to which recombinant human CETP was added decreased LPS uptake, TLR4 expression, NF-κB activation and IL-6 secretion. This raises the possibility for new therapeutic tools in sepsis while suggesting that lowering CETP by pharmacological inhibitors should be inconvenient in the context of sepsis and infectious diseases.
Insights
Cholesteryl ester transfer protein (CETP) enhances survival in sepsis by reducing inflammation. Lowering CETP may be detrimental for sepsis and infectious diseases.
Area of Science:
- Immunology
- Biochemistry
- Pathophysiology
Background:
- Sepsis is a life-threatening systemic inflammatory response to infection with high mortality.
- Mechanisms underlying sepsis pathogenesis remain incompletely understood, necessitating novel therapeutic targets.
Purpose of the Study:
- To investigate the role of cholesteryl ester transfer protein (CETP) in modulating the inflammatory response during sepsis.
- To evaluate the impact of CETP on survival rates and inflammatory profiles in a murine sepsis model.
Main Methods:
- Polymicrobial sepsis was induced in human CETP transgenic mice and wild-type (WT) control mice using cecal ligation and puncture (CLP).
- Peritoneal macrophages were isolated and stimulated with lipopolysaccharide (LPS) with or without recombinant CETP for phenotypic and functional analyses.
Main Results:
- CETP transgenic mice exhibited significantly higher survival rates compared to WT mice post-CLP.
- Lower plasma concentrations of interleukin-6 (IL-6) and reduced hepatic expression of toll-like receptor 4 (TLR4) and acyloxyacyl hydrolase (AOAH) were observed in CETP mice.
- Recombinant CETP treatment decreased LPS uptake, TLR4 expression, NF-κB activation, and IL-6 secretion in WT macrophages.
Conclusions:
- CETP plays a protective role in sepsis, attenuating the inflammatory response and improving survival.
- Pharmacological inhibition of CETP might be disadvantageous in managing sepsis and other infectious diseases.
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