Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis

Steeland, Sophie; Ryckeghem, Sara Van; Vandewalle, Jolien; Ballegeer, Marlies; Wonterghem, Elien Van; Eggermont, Melanie; Decruyenaere, Johan; Bus, Liesbet De; Libert, Claude; Vandenbroucke, Roosmarijn E.

doi:10.1097/ccm.0000000000002813

Cited by 14 publications

(19 citation statements)

References 46 publications

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“…In contrast to our observations [67], Ebach et al reported that TNFR1 KO mice had prolonged survival in CLP and they found that TNFR2 KO mice were more sensitive and had more severe hypothermia than WT mice [75]. When polymicrobial sepsis was initiated by i.p.…”

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsiscontrasting

confidence: 99%

“…Interestingly, TNFR1 -/-mice also experienced less sepsis-induced memory deficits, possibly by increased hippocampal expression of BDNF [71]. However, despite of these interesting observations, TNFR1 KO mice were not protected against very high LPS doses [39,63], which of 59 our lab also confirmed in previous research [67]. The previous models are sterile models, and observations in CLP, which is considered as the golden standard for human polymicrobial sepsis [72], or in colon ascendens stent peritonitis (CASP) left the scientific community with contradictory results regarding the different roles of TNFR1 and TNFR2 in real sepsis models.…”

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsissupporting

confidence: 79%

“…These data also suggest that lethality does not depend on TNF, but also other inflammatory mediators contribute to the LPS-induced lethality for instance IL-1β or matrix metalloproteinases (MMPs) [76]. Indeed, former research of the lab identified an important interplay between TNFR1 signaling and MMP8 in sepsis [67]. In sepsis patients, the serum levels of circulating sTNFR1 and MMP8 correlated positively with each other but also with the disease severity.…”

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsismentioning

confidence: 84%

“…At the level of the gut, Williams et al reported that TNFR1 is essential for LPS-induced gut injury by mediating apoptosis of intestinal epithelial cells (IECs) [64], and also in the TNF-induced lethal shock model, the complete survival benefit in TNFR1 KO mice was also attributed to the avoidance of TNFinduced gut permeability [38,65,66]. In addition to the benefits at the level of the gut, also the bloodcerebrospinal fluid (CSF) barrier permeability was less comprised in endotoxic TNFR1 KO mice [67]. This is an important observation, as preservation of the integrity of the brain barriers might overcome the occurrence of sepsis-associated encephalopathy (SAE) [68].…”

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsismentioning

confidence: 99%

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A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-TNF drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn’s disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the different (neurodegenerative) diseases that might benefit from selective approaches.

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Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsiscontrasting

confidence: 99%

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsissupporting

confidence: 79%

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsismentioning

confidence: 84%

Section: Differential Roles For Tnfr1 and Tnfr2 In Sepsismentioning

confidence: 99%

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A New Venue of TNF Targeting

Steeland

Libert

Vandenbroucke

2018

Preprint

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“…7,8 Inhibition of the production of proinflammatory cytokines is a promising approach for the treatment of sepsis. 9 Recent studies on the pathogenesis of sepsis revealed the participation of noncoding RNAs, such as microRNAs and long (>200 nt) noncoding RNAs (lncRNAs). 10,11 For instance, miR-27a upregulates the gene encoding TNF-a (TNFA) to relieve the inflammation of sepsis.…”

Section: Introductionmentioning

confidence: 99%

Long noncoding RNA TUG1 is downregulated in sepsis and may sponge miR-27a to downregulate tumor necrosis factor-α

et al. 2020

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Objectives: Bioinformatics analysis revealed a potential interaction between long noncoding (lnc) RNA TUG1 (taurine-upregulated gene 1) and microRNA (miR)-27a. miR-27a can promote sepsis by upregulating tumor necrosis factor-a (TNF-a). Our objective was to study the roles of TUG1 in sepsis. Methods: Plasma levels of TUG1 in patients with sepsis and in healthy controls were measured by quantitative PCR assay. The IntaRNA program was used to predict potential interactions between TUG1 mRNA and miR-27a. The interaction between TUG1 and miR-27a was further explored by transfecting TUG1 expression vector or miR-27a mimic into AC16 human cardiomyocytes, and apoptosis was evaluated by cell apoptosis assay. Results: TUG1 was downregulated in patients with sepsis. TUG1 was able to directly interact with miR-27a, but overexpression of TUG1 or miR-27a failed to affect the expression of each other. In contrast, TUG1 overexpression led to decreased levels of TNF-a, whereas miR-27a overexpression increased TNF-a in cardiomyocytes. Cell apoptosis analysis showed that TNF-a and miR-27a overexpression promoted apoptosis of cardiomyocytes induced by lipopolysaccharide. TUG1 overexpression had the opposite effect and attenuated the effects of TNF-a and miR-27a overexpression. Conclusion: We conclude that TUG1 is downregulated in sepsis and may act as a molecular "sponge" of miR-27a to downregulate TNF-a.

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Using the inbred mouse strain SPRET/EiJ to provide novel insights in inflammation and infection research

et al. 2018

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Inbred mouse strains derived from the species Mus spretus have been very informative in the study of certain gene polymorphisms in inflammation and infection. Based on our interest in sepsis, we used SPRET/EiJ mice and mapped several critical loci that are linked to sensitivity to cytokine-induced inflammation and endotoxemia. These studies were based on prominent phenotypes that have never been observed in strains derived from Mus musculus and we mapped them at a resolution that enables us to draw conclusions on the mechanisms. Now that the genome of SPRET/EiJ has been sequenced, and other tools have become available, it is time to revisit this strain and emphasize its advantages and disadvantages as a research tool and a discovery platform.

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Simultaneous Inhibition of Tumor Necrosis Factor Receptor 1 and Matrix Metalloproteinase 8 Completely Protects Against Acute Inflammation and Sepsis

Abstract: Inhibition of matrix metalloproteinase 8 and tumor necrosis factor receptor 1 might have therapeutic potential to treat sepsis and proof-of-principle was provided as therapeutics that inhibit both tumor necrosis factor receptor 1 and matrix metalloproteinase 8 are effective in CLP.

Cited by 14 publications

References 46 publications

A New Venue of TNF Targeting

A New Venue of TNF Targeting

Long noncoding RNA TUG1 is downregulated in sepsis and may sponge miR-27a to downregulate tumor necrosis factor-α

Using the inbred mouse strain SPRET/EiJ to provide novel insights in inflammation and infection research

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