Simultaneous Targeting of IL-1 and IL-18 Is Required for Protection against Inflammatory and Septic Shock

Berghe, Tom Vanden; Demon, Dieter; Bogaert, Pieter; Vandendriessche, Benjamin; Goethals, A.; Depuydt, Ben; Vuylsteke, Marnik; Roelandt, Ria; Wonterghem, Elien Van; Vandenbroecke, Jill; Choi, Sze Men; Meyer, Evelyne; Krautwald, Stefan; Declercq, Wim; Takahashi, Nozomi; Cauwels, Anje; Vandenabeele, Peter

doi:10.1164/rccm.201308-1535oc

Cited by 149 publications

(78 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5D). These results are consistent with previous reports that IL-18 can drive IL-1 and that blockade of both IL-18 and IL-1 is associated with an increase in sepsis survival (11) and substantially bridge the gaps in our mechanistic understanding of how IL-18 participates in this inflammatory pathway.…”

Section: Resultssupporting

confidence: 92%

“…In contrast, some studies have shown a critical positive role for IL-18 in the adult host response to Pseudomonas pneumonia (3,10). The survival benefits of combined IL-18/ IL-1β targeting were demonstrated recently in septic shock, but that study did not investigate the primary contributor to deleterious outcomes in murine sepsis, nor did they establish the mechanism of effect (11).…”

mentioning

confidence: 98%

See 1 more Smart Citation

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Wynn

Wilson

Hawiger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Interleukin (IL)-18 is an important effector of innate and adaptive immunity, but its expression must also be tightly regulated because it can potentiate lethal systemic inflammation and death. Healthy and septic human neonates demonstrate elevated serum concentrations of IL-18 compared with adults. Thus, we determined the contribution of IL-18 to lethality and its mechanism in a murine model of neonatal sepsis. We find that IL-18-null neonatal mice are highly protected from polymicrobial sepsis, whereas replenishing IL-18 increased lethality to sepsis or endotoxemia. Increased lethality depended on IL-1 receptor 1 (IL-1R1) signaling but not adaptive immunity. In genome-wide analyses of blood mRNA from septic human neonates, expression of the IL-17 receptor emerged as a critical regulatory node. Indeed, IL-18 administration in sepsis increased IL-17A production by murine intestinal γδT cells as well as Ly6G + myeloid cells, and blocking IL-17A reduced IL-18-potentiated mortality to both neonatal sepsis and endotoxemia. We conclude that IL-17A is a previously unrecognized effector of IL-18-mediated injury in neonatal sepsis and that disruption of the deleterious and tissue-destructive IL-18/IL-1/IL-17A axis represents a novel therapeutic approach to improve outcomes for human neonates with sepsis.IL-18 | IL-17 | sepsis | neonate | pathogenesis

show abstract

Section: Resultssupporting

confidence: 92%

mentioning

confidence: 98%

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Wynn

Wilson

Hawiger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In contrast to humans mice are inbreed littermates with no genetic variation and cytokine differences should have been detected. Other studies could detect differences in TNF-α expression between KO and wild type mice of other genes [38]. Therefore AQP5 might not influence TNF-α pathway and other inflammatory proteins might be responsible for the differences occurring in Aqp5 -KO and WT animals.…”

Section: Discussionmentioning

confidence: 98%

AQP5-1364A/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study

et al. 2016

View full text Add to dashboard Cite

BackgroundThe C-allele of the aquaporin (AQP5) -1364A/C polymorphism is associated with decreased AQP5 expression but increased 30-day survival in patients with severe sepsis. AQP5 expression might affect survival via an impact on cell migration. Consequently, we tested the hypothesis that (1) Aqp5 knockout (KO) compared to wild type (WT) mice show an increased survival following lipopolysaccharide (LPS) administration, and that (2) AQP5 expression and the AQP5 -1364A/C polymorphism alters immune cell migration.MethodsWe investigated Aqp5-KO and wild type mice after intraperitoneal injection of either E.coli lipopolysaccharide (LPS, serotype O127:B8, 20 mg/kg) or saline. Furthermore, neutrophils of volunteers with the AA-AQP5 or AC/CC-AQP5- genotype were incubated with 10−8 M Chemotactic peptide (fMLP) and their migration was assessed by a filter migration assay. Additionally, AQP5 expression after fMLP incubation was analyzed by RT-PCR and Western blot. Moreover, migration of AQP5 overexpressing Jurkat cells was studied after SDF-1α-stimulation. We used exact Wilcoxon–Mann–Whitney tests; exact Wilcoxon signed-rank tests and the Kaplan–Meier estimator for statistical analysis.ResultsFifty-six percent of Aqp5-KO but only 22% of WT mice survived following LPS-injection. WT mice showed increased neutrophil migration into peritoneum and lung compared to Aqp5-KO mice. Target-oriented migration of neutrophils was seen after 0.5 h in AA-genotype cells but only after 1.5 h in AC/CC-genotype cells, with a threefold lower migrating cell count. AQP5 overexpressing Jurkat cells showed a 2.4 times stronger migration compared to native Jurkat cells.ConclusionThe AQP5 genotype may influence survival following LPS by altering neutrophil cell migration. Trial registration DRKS00010437. Retrospectively registered 26 April 2016Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1079-2) contains supplementary material, which is available to authorized users.

show abstract

“…Consistent with this, LPS-injected caspase-4 transgenic mice secreted higher levels of IL-1β and IL-18 initially, and interestingly, in contrast to in vitro assay, other cytokines were significantly induced, indicating the presence of complex cytokine cross-stimulation between cells and tissues in vivo . More recently, secretion of IL-1β and IL-18 has been shown to contribute to lethality induced by low doses of LPS in mice (37), although they may not mediate lethality to high doses of LPS (14). Our data showing that the secretion of IL-1β and IL-18 represents an immediate early response in caspase-4 transgenic mice may partially explain the mechanism of the increased lethality (Fig.…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Human Caspase-4 in Endotoxin Sensitivity

Kajiwara

Schiff

Voloudakis

et al. 2014

The Journal of Immunology

101

View full text Add to dashboard Cite

Response to endotoxins is an important part of the organismal reaction to gram-negative bacteria, and plays a critical role in sepsis and septic shock, as well as other conditions such as metabolic endotoxemia. Humans are generally more sensitive to endotoxins when compared to experimental animals such as mouse. Inflammatory caspases mediate endotoxin-induced interelukin-1β (IL-1β) secretion and lethality in mouse, and caspase-4 is an inflammatory caspase that is found in the human, and not mouse, genome. To test whether caspase-4 is involved in endotoxin sensitivity, we developed a transgenic mouse expressing human caspase-4 in its genomic context. Caspase-4 transgenic mice exhibited significantly higher endotoxin sensitivity, as measured by enhanced cytokine secretion and lethality following lipopolysaccharide (LPS) challenge. Using bone marrow-derived macrophages (BMDMs), we then observed that caspase-4 can support activation of caspase-1 and secretion of IL-1β and IL-18 in response to priming signals (LPS or Pam3CSK4) alone, without the need for second signals to stimulate the assembly of the inflammasome. These findings indicate that the regulation of caspase-1 activity by human caspase-4 could represent unique mechanism in humans, as compared to laboratory rodents, and may partially explain the higher sensitivity to endotoxins observed in humans. Regulation of the expression, activation, or activity of caspase-4 therefore represent therapeutic targets for systemic inflammatory response syndrome (SIRS), sepsis, septic shock, and related disorders.

show abstract

Simultaneous Targeting of IL-1 and IL-18 Is Required for Protection against Inflammatory and Septic Shock

Abstract: Our data point toward the therapeutic potential of neutralizing IL-1 and IL-18 simultaneously in sepsis, rather than inhibiting the upstream inflammatory caspases.

Cited by 149 publications

References 54 publications

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18

AQP5-1364A/C polymorphism and the AQP5 expression influence sepsis survival and immune cell migration: a prospective laboratory and patient study

A Critical Role for Human Caspase-4 in Endotoxin Sensitivity

Contact Info

Product

Resources

About