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.
Pharmacology, Toxicology and Pharmaceutical Science
3
3%
Other
12
11%
Unknown
38
35%
Attention Score in Context
Attention Score in Context
This research output has an Altmetric Attention Score of 34. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 03 October 2023.
All research outputs
#1,496,889
of 34,297,219 outputs
Outputs from Proceedings of the National Academy of Sciences of the United States of America
#20,189
of 118,714 outputs
Outputs of similar age
#19,029
of 337,760 outputs
Outputs of similar age from Proceedings of the National Academy of Sciences of the United States of America
#310
of 831 outputs
Altmetric has tracked 34,297,219 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 95th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 118,714 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 39.9. This one has done well, scoring higher than 82% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 337,760 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 94% of its contemporaries.
We're also able to compare this research output to 831 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 62% of its contemporaries.
