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Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18
- Source :
- Proceedings of the National Academy of Sciences of the United States of America, vol 113, iss 19
- Publication Year :
- 2016
- Publisher :
- eScholarship, University of California, 2016.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
Systemic inflammation
Inbred C57BL
sepsis
Mice
0302 clinical medicine
Monoclonal
2.1 Biological and endogenous factors
Molecular Targeted Therapy
Aetiology
Pediatric
Multidisciplinary
Neonatal sepsis
Effector
pathogenesis
Interleukin-17
Interleukin-18
Antibodies, Monoclonal
Interleukin
Hematology
Acquired immune system
Survival Rate
IL-17
Treatment Outcome
Infectious Diseases
Interleukin 18
Female
Interleukin 17
medicine.symptom
Neonatal Sepsis
Infection
IL-18
Biology
Antibodies
Sepsis
03 medical and health sciences
Clinical Research
medicine
Animals
Inflammatory and immune system
medicine.disease
Newborn
Mice, Inbred C57BL
030104 developmental biology
Good Health and Well Being
Animals, Newborn
Immunology
neonate
030215 immunology
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America, vol 113, iss 19
- Accession number :
- edsair.doi.dedup.....4588e6701efa09427bb5837334d27124