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

Proc Natl Acad Sci U S A. 2016 May 10;113(19):E2627-35. doi: 10.1073/pnas.1515793113. Epub 2016 Apr 25.

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.

Keywords: IL-17; IL-18; neonate; pathogenesis; sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Antibodies, Monoclonal / therapeutic use
  • Female
  • Interleukin-17 / antagonists & inhibitors*
  • Interleukin-17 / immunology*
  • Interleukin-18 / immunology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Targeted Therapy / methods
  • Neonatal Sepsis / immunology*
  • Neonatal Sepsis / pathology
  • Neonatal Sepsis / therapy*
  • Survival Rate*
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Interleukin-17
  • Interleukin-18