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

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

Author information

1
Department of Pediatrics, University of Florida, Gainesville, FL 32610; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610; james.wynn@peds.ufl.edu.
2
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232;
3
Department of Medicine, Vanderbilt University, Nashville, TN 37232; Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232;
4
Division of Dermatology, University of California, Los Angeles, CA 90095;
5
Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;
6
Department of Pediatrics, University of Florida, Gainesville, FL 32610;
7
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229;
8
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232;
9
Department of Surgery, University of Florida College of Medicine, Gainesville, FL 32610;
10
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL 32610;
11
Department of Pediatrics, University of Iowa, Iowa City, IA 52242;
12
Center for Inflammation & Mucosal Immunology, University of Florida, Gainesville, FL 32610.
13
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232; Department of Pediatrics, Vanderbilt University, Nashville, TN 37232;

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

PMID:
27114524
PMCID:
PMC4868456
DOI:
10.1073/pnas.1515793113
[Indexed for MEDLINE]
Free PMC Article

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